MET fusions are targetable genomic variants in the treatment of advanced malignancies.

Targeted therapy for malignancies has developed rapidly in recent years, benefiting patients harboring genetic mutations sensitive to relevant tyrosine kinase inhibitors (TKIs). With the development of targeted sequencing techniques, an increasing number of detectable genomic alterations in malignancies, including MET fusions, have been revealed. MET fusions, although rare among malignancies, might be functional driver genes that participate in activating downstream signaling pathways and promoting cell proliferation. Therefore, it is believed that MET fusions could be targetable genomic variants of MET, and inhibition of MET is considered an optionable therapeutic choice for patients harboring MET fusions. According to the summary presented in this review, we recommend MET-TKIs as suitable treatment agents for patients harboring primary MET fusions. For patients harboring acquired MET fusions after the development of resistance to TKIs targeting primary genomic alterations, such as sensitive EGFR mutations, treatment with a MET-TKI alone or in combination with TKIs targeting primary genomic alterations, such as EGFR-TKIs, is hypothesized to be a reasonable option for salvage treatment. In summary, MET fusions, despite their low incidence, should be taken into consideration when developing treatment strategies for cancer patients.

Neoadjuvant PD-(L)1 blockade plus platinum-based chemotherapy for potentially resectable oncogene-positive non-small cell lung cancer.

BACKGROUND: Whether programmed cell death-1/ligand-1 (PD-1/PD-L1) blockade-based neoadjuvant treatment may benefit locally advanced oncogene-mutant non-small cell lung cancer (NSCLC) patients remains controversial. This retrospective study was designed to observe the efficacy and safety of neoadjuvant PD-1/PD-L1 blockade plus chemotherapy versus chemotherapy and corresponding tyrosine kinase inhibitors (TKIs) in patients with resectable oncogene-positive NSCLC. METHODS: Patients with potential resectable NSCLC harbouring oncogene alterations who had received neoadjuvant treatment were retrospectively recruited, and an oncogene-negative cohort of patients who received neoadjuvant PD-(L)1 blockade-based neoadjuvant treatment was reviewed for comparison during the same period. The primary aim was to observe the treatment efficacy and event-free survival (EFS) of these agents. Safety profile, molecular target, and immunologic factor data, including PD-L1 expression and tumour mutational burden (TMB), were also obtained. RESULTS: A total of 46 patients were recruited. Thirty-one of them harboured oncogene alterations, including EGFR, KRAS, ERBB2, ROS1, MET, RET, ALK, and FGFR3 alterations. Among the oncogene-positive patients, 18 patients received neoadjuvant PD-(L)1 blockade immunotherapy plus chemotherapy (oncogene-positive IO group), 13 patients were treated with neoadjuvant chemotherapy and/or corresponding TKIs or TKIs alone (oncogene-positive chemo/TKIs group), and the other 15 patients were oncogene negative and received neoadjuvant PD-(L)1 blockade plus chemotherapy (oncogene-negative IO group). The pathological complete response (pCR) and major pathological response (MPR) rates were 22.2% (4 of 18) and 44.4% (8 of 18) in the oncogene-positive IO group, 0% (P = 0.120) and 23.1% (3 of 13) (P = 0.276) in the oncogene-positive chemo/TKIs group, and 46.7% (7 of 15) (P = 0.163) and 80.0% (12 of 15) (P = 0.072) in the oncogene-negative IO group, respectively. By the last follow-up, the median EFS time had not reached in the oncogene-positive IO group, and was 29.5 months in the oncogene-positive chemo/TKIs group and 38.4 months in the oncogene-negative IO group. CONCLUSION: Compared with chemotherapy/TKIs treatment, neoadjuvant treatment with PD-(L)1 blockade plus platinum-based chemotherapy was associated with higher pCR/MPR rates in patients with partially resectable oncogene-mutant NSCLC, while the pCR/MPR rates were lower than their oncogene-negative counterparts treated with PD-(L)1 blockade-based treatment. Specifically, oncogene alteration types and other predictors of response to immunotherapy should be taken into account in clinical practice.

Identification of MET fusions as novel therapeutic targets sensitive to MET inhibitors in lung cancer.

INTRODUCTION: Alterations in the MET gene, including amplifications and exon 14 skipping mutations, have been identified as actionable oncogenic alterations. However, MET fusions are rarely detected in lung cancer, and their sensitivity to therapeutics has not been systematically analyzed. METHODS: The data from 30876 lung cancer patients from the LAVA database and 7966 patients from cBioPortal database were screened. Basic demographic and clinical information for the patients harboring MET fusions were collected. A lung squamous cell cancer patient harboring a novel EML4-MET fusion was treated with crizotinib. Additionally, a literature review was performed to summarize the cases of patients harboring MET fusions and their treatment information. RESULTS: MET fusions were found in only 0.2% to 0.3% of lung cancer patients and appeared in almost all exons of the MET gene. Intragenic MET fusions were found in 52.6% (41/78) of the included patients. Crizotinib was effective for MET fusions, including a novel identified EML4-MET fusion, even after the failure of multiple lines of treatment. This result suggested that acquired MET fusions become more regionally selective, as they usually occurred in exons encoding the extracellular region. Interestingly, the MET-fused genes in primary MET fusions or acquired MET fusions were very different, which indicated the different functions and influences of the disease. CONCLUSION: MET fusions are rare, and half of the fusion types were intragenic fusions. Lung cancer patients harboring primary or acquired MET fusions could benefit from crizotinib. In addition, EML4-MET was first reported in this study as a novel MET fusion type.

Neoadjuvant toripalimab plus platinum-paclitaxel chemotherapy in stage II-III non-small cell lung cancer: a single-center, single-arm, phase I study in China.

BACKGROUND: Neoadjuvant and adjuvant immune checkpoint inhibitor treatments for non-small cell lung cancer (NSCLC) patients with resectable disease have presented promising results. This is a phase I study to evaluate the safety and efficacy of neoadjuvant toripalimab in combination with chemotherapy for NSCLC. METHODS: Treatment-naive patients with resectable NSCLC (stage II-IIIB) received two to four cycles of toripalimab (240 mg, intravenously, q3w) combined with platinum-paclitaxel chemotherapy. Surgical operation was performed approximately 4 weeks after the last cycle. The primary end point was safety. The efficacy endpoints included radiographic and pathological response rates, expression of programmed death ligand 1 (PD-L1) and molecular targets. RESULTS: A total of 11 patients were enrolled, consisting of 2 patients (18%) with adenocarcinoma and 9 patients (82%) with squamous cell carcinoma. All patients received two to four cycles of toripalimab plus chemotherapy and underwent radical resection. Regarding safety, 5 of 11 patients (45%) had neoadjuvant treatment-related adverse events, and 1 patient (9%) experienced grade 3 or worse treatment-related adverse events. Radiographic partial response was achieved in 10 patients, with an objective response rate of 91%. Among 11 patients, 6 (55%) achieved pathological complete response, including 1 PD-L1-negative patient. CONCLUSION: Neoadjuvant toripalimab plus platinum-paclitaxel chemotherapy was tolerable and induced a pathological complete response in 55% of resectable NSCLC patients.

Aberrant circulating tumor DNA methylation and exosomal microRNA biomarkers for early detection of colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) became the third most commonly diagnosed malignancy and the second leading cause of cancer death in 2020. However, the rates of early screening and early diagnosis for CRC remain unsatisfactory. Thus, it is essential to explore the initiating factors of CRC and strategies for its early diagnosis. Research progress in liquid biopsy has led to the finding that circulating tumor-derived DNA (ctDNA) and exosomes play vital roles in early detection of CRC. THE APPLICATIONS OF LIQUID BIOPSY FOR EARLY DETECTION OF COLORECTAL CANCER: Moreover, the increased understanding of epigenetics has highlighted the role of ctDNA methylation in CRC carcinogenesis, and the detection of aberrant ctDNA methylation markers is a feasible strategy for diagnosis of early-stage CRC. Among exosomal markers, microRNAs (miRNAs) are abundant and are the most researched. Upregulated or downregulated expression of exosome-derived miRNAs can indicate the occurrence of early-stage CRC. FUTURE PERSPECTIVE: The current research progress on aberrant ctDNA methylation and tumor exosomal miRNA biomarkers in early detection of CRC is summarized in this review, and the advantages and shortcomings of the methods are discussed.

Anlotinib Combined with Toripalimab as Second-Line Therapy for Advanced, Relapsed Gastric or Gastroesophageal Junction Carcinoma.

Our study aimed to explore the efficacy and safety of anlotinib-toripalimab combination therapy as a second-line treatment for advanced relapsed gastric or gastroesophageal junction carcinoma (GC/GEJC). In this single arm, single-center extension clinical trial, patients with advanced relapsed GC/GEJC received toripalimab (240 mg, intravenously over 60 minutes, once every 2 weeks) plus anlotinib (12 mg/day, orally, 2 weeks on and 1 week off, every 3 weeks) as second-line therapy. There were 29 patients who achieved partial response, and the ORR was 32.3% (95% CI, 26.6%-38.5%). Grade 3 treatment-related adverse events (TRAEs) were recorded in 7 participants (11.3%), all of which were manageable. The PFS and OS were 4.0 and 11.1 months, respectively. Patients with programmed death-ligand 1 (PD-L1) positive expression showed numerically longer OS than the negative ones although the difference was not significantly. The tumor mutational burden-high (TMB-H) group showed a significantly better OS (P = .05) than the TMB-Low (TMB-L) group. Next-generation sequencing (NGS) revealed that fibroblast growth factor receptor 2 (FGFR2) mutations positively correlated with target lesion reduction (odds ratio [OR] = 0.14; P = .02). The new regimen increased tumor-infiltration of CD8+ T and CD3+ T cells. Furthermore, a patient-derived organoid (PDO) study indicated that anlotinib could promote an immune-supportive tumor microenvironment. As conclusion, the anlotinib-toripalimab combination showed promising efficacy and favorable safety as a second-line treatment for advanced, relapsed GC/GEJC. The PD-L1 expression, TMB, and FGFR2 mutation are potential biomarkers for predicting the efficacy of this regimen (ClinicalTrials.gov registration number: NCT04713059).

The role of RICTOR amplification in targeted therapy and drug resistance.

The emergence of tyrosine kinase inhibitors (TKIs) has changed the current treatment paradigm and achieved good results in recent decades. However, an increasing number of studies have indicated that the complex network of receptor tyrosine kinase (RTK) co-activation could influence the characteristic phenotypes of cancer and the tumor response to targeted treatments. One of strategies to blocking RTK co-activation is targeting the downstream factors of RTK, such as PI3K-AKT-mTOR pathway. RICTOR, a core component of mTORC2, acts as a key effector molecule of the PI3K-AKT pathway; its amplification is often associated with poor clinical outcomes and resistance to TKIs. Here, we discuss the biology of RICTOR in tumor and the prospects of targeting RICTOR as a complementary therapy to inhibit RTK co-activation.

Primary resistance to first-generation EGFR-TKIs induced by MDM2 amplification in NSCLC.

INTRODUCTION: Targeted therapy for NSCLC is rapidly evolving. EGFR-TKIs benefit NSCLC patients with sensitive EGFR mutations and significantly prolong survival. However, 20-30% of patients demonstrate primary resistance to EGFR-TKIs, which leads to the failure of EGFR-TKI treatment. The mechanisms of primary resistance to EGFR-TKIs require further study. METHODS: Targeted sequencing was used for the detection of genomic alterations among patients in our center. Regular cell culture and transfection with plasmids were used to establish NSCLC cell lines over-expressing MDM2 and vector control. We used the MTT assays to calculate the inhibition rate after exposure to erlotinib. Available datasets were used to determine the role of MDM2 in the prognosis of NSCLC. RESULTS: Four patients harboring concurrent sensitive EGFR mutations and MDM2 amplifications demonstrated insensitivity to EGFR-TKIs in our center. In vitro experiments suggested that MDM2 amplification induces primary resistance to erlotinib. Over-expressed MDM2 elevated the IC50 value of erlotinib in HCC2279 line and reduced the inhibition rate. In addition, MDM2 amplification predicted a poor prognosis in NSCLC patients and was associated with a short PFS in those treated with EGFR-TKIs. The ERBB2 pathway was identified as a potential pathway activated by MDM2 amplification could be the focus of further research. CONCLUSION: MDM2 amplification induces the primary resistance to EGFR-TKIs and predicts poor prognosis in NSCLC patients. MDM2 may serve as a novel biomarker and treatment target for NSCLC. Further studies are needed to confirm the mechanism by which amplified MDM2 leads to primary resistance to EGFR-TKIs.

Subunits of ARID1 serve as novel biomarkers for the sensitivity to immune checkpoint inhibitors and prognosis of advanced non-small cell lung cancer.

INTRODUCTION: Patients with advanced non-small cell lung cancer (NSCLC) benefit from treatment with immune checkpoint inhibitors (ICIs). Biomarkers such as programmed death-ligand 1 (PD-L1), the tumor mutational burden (TMB) and the mismatch repair (MMR) status are used to predict the prognosis of ICIs therapy. Nevertheless, novel biomarkers need to be further investigated, and a systematic prognostic model is needed for the evaluation of the survival risks of ICIs treatment. METHODS: A cohort of 240 patients who received ICIs from the cBioPortal for Cancer Genomics was evaluated in this research. Clinical information and targeted sequencing data were acquired for analyses. The Kaplan-Meier plot method was used to perform survival analyses, and selected variables were then confirmed by a novel nomogram constructed by the "rms" package of R software. RESULTS: Seven percent of the NSCLC patients harbored ARID1A mutations, while 4% of the NSCLC patients harbored ARID1B mutations. Mutations in ARID1A and ARID1B were confirmed to be associated with sensitivity to ICIs. Patients harboring these mutations were found to have a better response to treatment (ARID1A: P = 0.045; ARID1B: P = 0.034) and prolonged progression-free survival (ARID1B: P = 0.032). Here, a novel nomogram was constructed to predict the prognosis of ICIs treatment. Elevation of the TMB, enhanced expression of PD-L1 and activation of the antigen presentation process and cellular immunity were found to be correlated with ARID1A and ARID1B mutations. CONCLUSION: ARID1A and ARID1B could serve as novel biomarkers for the prognosis and sensitivity to ICIs of advanced NSCLC.

Advancement in research and therapy of NF1 mutant malignant tumors.

The NF1 gene encodes neurofibromin, which is one of the primary negative regulatory factors of the Ras protein. Neurofibromin stimulates the GTPase activity of Ras to convert it from an active GTP-bound form to its inactive GDP-bound form through its GTPase activating protein-related domain (GRD). Therefore, neurofibromin serves as a shutdown signal for all vertebrate RAS GTPases. NF1 mutations cause a resultant decrease in neurofibromin expression, which has been detected in many human malignancies, including NSCLC, breast cancer and so on. NF1 mutations are associated with the underlying mechanisms of treatment resistance discovered in multiple malignancies. This paper reviews the possible mechanisms of NF1 mutation-induced therapeutic resistance to chemotherapy, endocrine therapy and targeted therapy in malignancies. Then, we further discuss advancements in targeted therapy for NF1-mutated malignant tumors. In addition, therapies targeting the downstream molecules of NF1 might be potential novel strategies for the treatment of advanced malignancies.

Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis.

BACKGROUND: The prognostic significance of TP53 concurrent mutations in patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)- mutated advanced non-small-cell lung cancer (NSCLC) who received EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs based targeted therapy remains controversial. Therefore, the present meta-analysis was performed to investigate the association between TP53 concurrent mutations and prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK-TKIs treatments. METHODS: Eligible studies were identified by searching the online databases PubMed, Embase, Medline, The Cochrane library and Web of Science. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to clarify the correlation between TP53 mutation status and prognosis of patients. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: In total, 15 studies with 1342 patients were included for final analysis. Overall, concurrent TP53 mutation was associated with unfavorable progression-free survival (PFS) (HR = 1.88, 95%CI: 1.59-2.23, p < 0.001, I2 = 0.0%, P = 0.792) and overall survival (OS) (HR = 1.92, 95%CI: 1.55-2.38, p < 0.001, I2 = 0.0%, P = 0.515). Subgroup analysis based on type of targeted therapy (EGFR-TKIs or ALK-TKIs, pathological type of cancer (adenocarcinoma only or all NSCLC subtypes) and line of treatment (first-line only or all lines) all showed that TP53 mutations was associated with shorter survivals of patients with EGFR-TKIs or ALK-TKIs treatments. Particularly, in patients with first-line EGFR-TKIs treatment, significantly poorer prognosis was observed in patients with TP53 concurrent mutations (pooled HR for PFS: 1.69, 95% CI 1.25-2.27, P < 0.001, I2 = 0.0%, P = 0.473; pooled HR for OS: 1.94, 95% CI 1.36-2.76, P < 0.001, I2 = 0.0%, P = 0.484). Begg's funnel plots and Egger's tests indicated no significant publication bias in this study. CONCLUSIONS: This meta-analysis indicated that concurrent TP53 mutations was a negative prognostic factor and associated with poorer outcomes of patients with EGFR-TKIs or ALK-TKIs treatments in advanced NSCLC. In addition, our study provided evidence that TP53 mutations might be involved in primary resistance to EGFR-TKIs treatments in patients with sensitive EGFR mutations in advanced NSCLC.

The role of CD28 in the prognosis of young lung adenocarcinoma patients.

BACKGROUND: The prognosis of lung cancer was found to be associated with a series of biomarkers related to the tumor immune microenvironment (TIME), which can modulate the biological behaviors and consequent outcomes of lung cancer. Therefore, establishing a prognostic model based on the TIME for lung cancer patients, especially young patients with lung adenocarcinoma (LUAD), is urgently needed. METHODS: In all, 809 lung cancer patients from the TCGA database and 71 young patients with LUAD in our center were involved in this study. Univariate and multivariate analysis based on clinical characteristics and TIME-related expression patterns (as evaluated by IHC) were performed to estimate prognosis and were verified by prognostic nomograms. RESULTS: Both LUAD and lung cancer patients with high CD28 expression had shorter disease-free survival (DFS) (P = 0.0011; P = 0.0001) but longer overall survival (OS) (P = 0.0001; P = 0.0282). TIME-related molecules combined with clinical information and genomic signatures could predict the prognosis of young patients with LUAD with robust efficiency and could be verified by the established nomogram based on the Cox regression model. In addition, CD28 expression was correlated with an abundance of lymphocytes and could modulate the TIME. Higher CD28 levels were observed in primary tumors than in metastatic tissues. CONCLUSION: TIME-related molecules were identified as compelling biomarkers for predicting the prognosis of lung cancer, especially in a cohort of young patients. Furthermore, CD28, which is associated with poor DFS but long OS, might participate in the modulation of the TIME and has a different role in the prognosis of young patients with LUAD.

Concordance Study Between IBM Watson for Oncology and Clinical Practice for Patients with Cancer in China.

BACKGROUND: IBM Watson for Oncology (WFO), which can use natural language processing to evaluate data in structured and unstructured formats, has begun to be used in China. It provides physicians with evidence-based treatment options and ranks them in three categories for treatment decision support. This study was designed to examine the concordance between the treatment recommendation proposed by WFO and actual clinical decisions by oncologists in our cancer center, which would reflect the differences of cancer treatment between China and the U.S. PATIENTS AND METHODS: Retrospective data from 362 patients with cancer were ingested into WFO from April 2017 to October 2017. WFO recommendations were provided in three categories: recommended, for consideration, and not recommended. Concordance was analyzed by comparing the treatment decisions proposed by WFO with those of the multidisciplinary tumor board. Concordance was achieved when the oncologists' treatment decisions were in the recommended or for consideration categories in WFO. RESULTS: Ovarian cancer showed the highest concordance, which was 96%. Lung cancer and breast cancer obtained a concordance of slightly above 80%. The concordance of rectal cancer was 74%, whereas colon cancer and cervical cancer showed the same concordance of 64%. In particular, the concordance of gastric cancer was very low, only 12%, and 88% of cases were under physicians choice. CONCLUSION: Different cancer types showed different concordances, and only gastric cancers were significantly less likely to be concordant. Incidence and pharmaceuticals may be the major cause of discordance. To be comprehensively and rapidly applied in China, WFO needs to accelerate localization. ClinicalTrials.gov Identifier: NCT03400514. IMPLICATIONS FOR PRACTICE: IBM Watson for Oncology (WFO) has begun to be used in China. In this study, concordance was examined between the treatment recommendation proposed by WFO and clinical decisions for 362 patients in our cancer center, which could reflect the differences of cancer treatment between China and the U.S. Different cancer types showed different concordances, and only gastric cancers were significantly less likely to be concordant. Incidence and pharmaceuticals may be the major causes of discordance. To be comprehensively and rapidly applied in China, WFO needs to accelerate localization. This study may have a significant effect on application of artificial intelligence systems in China.

The role of MDM2 amplification and overexpression in therapeutic resistance of malignant tumors.

The MDM2 protein encoded by the mouse double minute 2 (MDM2) gene is the primary negative regulatory factor of the p53 protein. MDM2 can ligate the p53 protein via its E3 ubiquitin ligase, and the ubiquitinated p53 can be transferred to the cytoplasm and degraded by proteasomes. Therefore, MDM2 can maintain the stability of p53 signaling pathway. MDM2 amplification has been detected in many human malignancies, including lung cancer, colon cancer and other malignancies. MDM2 overexpression is associated with chemotherapeutic resistance in human malignancies. The mechanisms of chemotherapeutic resistance by MDM2 overexpression mainly include the p53-MDM2 loop-dependent and p53-MDM2 loop-independent pathways. But the role of MDM2 overexpression in tyrosine kinase inhibitors resistance remains to be further study. This paper reviews the possible mechanisms of therapeutic resistance of malignancies induced by MDM2 amplification and overexpression, including chemotherapy, radiotherapy, targeted agents and hyperprogressive disease of immunotherapy. Besides, MDM2-targeted therapy may be a potential new strategy for treating advanced malignancies.

Tunicamycin inhibits cell proliferation and migration in hepatocellular carcinoma through suppression of CD44s and the ERK1/2 pathway.

Tunicamycin (TM) is an N-linked glycosylation (NLG) inhibitor with strong antitumor activity, the exact underlying molecular mechanism of which remains to be elucidated. In our previous studies, we found that TM reversed drug resistance and improved the efficacy of combination treatments for hepatocellular carcinomas (HCC). Here, we investigated the effects of TM on HCC cell proliferation and migration as well as the mechanism of those effects. Our results showed that TM inhibited cell proliferation and migration as well as induced apoptosis of hepatocellular carcinoma cells. TM inhibited proliferation of HCC cells by inducing cell apoptosis and cell cycle arrest at the G2/M phase. Meanwhile, TM inhibited migration of HCC cells by suppressing CD44s-mediated epithelial-mesenchymal transition (EMT). TM inhibited migration and invasion of HCC cells by decreasing CD44 expression and altering its glycosylation. In addition, CD44s is involved in promoting EMT and is associated with a poor prognosis in HCC patients. Overexpression of CD44s promoted tumor migration and activated phosphorylation of ERK1/2 in HCC cells, whereas TM inhibited CD44s overexpression-associated cell migration. The ability of TM to inhibit cell migration and invasion was enhanced or reversed in CD44s knockdown cells and cells overexpressing CD44s, respectively. The MEK/ERK inhibitor U0126 and TM inhibited hyaluronic acid-induced cell migration in HCC cells. Furthermore, TM inhibited exogenous transforming growth factor beta (TGF-ß)-mediated EMT by an ERK1/2-dependent mechanism and restored the TGF-ß-mediated loss of E-cadherin. In summary, our study provides evidence that TM inhibits proliferation and migration of HCC cells through inhibition of CD44s and the ERK1/2 signaling pathway.

Comprehensive Molecular Characterization of Young Chinese Patients with Lung Adenocarcinoma Identified a Distinctive Genetic Profile.

BACKGROUND: Occurrence at a younger age has been demonstrated to be associated with a distinct biology in non-small cell lung cancer. However, genomics and clinical characteristics among younger patients with lung adenocarcinoma remain to be determined. Here we studied the potentially targetable genetic alterations by next-generation sequencing (NGS) assay in young Chinese patients with lung adenocarcinoma. MATERIALS AND METHODS: Seventy-one surgically resected lung adenocarcinoma tissue samples from patients aged less than 45 years were collected with informed consent from all patients. Targeted NGS assays were used to identify actionable genetic alterations in the cancer tissues. Additionally, the genomic and clinicopathologic characteristics of 106 patients with lung adenocarcinoma who received NGS testing over the same period were analyzed retrospectively. RESULTS: The frequencies of targetable genetic alterations in 177 patients with lung adenocarcinoma were analyzed by defined age categories, which unveiled a distinctive molecular profile in the younger group, aged less than 45 years. Notably, higher frequency of ALK and HER2 genetic alterations were associated with young age. However, a reverse trend was observed for KRAS, STK11 and EGFR exon 20 mutations, which were more frequently identified in the older group, aged more than 46 years. Furthermore, concurrent EGFR/TP53 mutations were much more prevalent in the younger patients (81.6% vs. 46.8%), which might have a poor response to treatment with epidermal growth factor receptor tyrosine kinase inhibitor. CONCLUSION: In this study, NGS assay revealed a distinctive genetic profile in younger patients with adenocarcinoma. High frequency of concurrent EGFR/TP53 mutations was found in the younger patients, which especially warranted personalized treatment in this population. IMPLICATIONS FOR PRACTICE: Further investigation is needed to understand the genomics and clinical characteristics of young patients with lung adenocarcinoma. In the present study, hybrid capture-based next-generation sequencing assays were used to identify targeted genetic alterations in young lung adenocarcinoma patients. Young patients with lung adenocarcinoma, aged less than 45 years, harbored a higher frequency of ALK and HER2 genetic alterations compared with patients aged more than 46 years. Dramatically, concurrent EGFR/TP53 mutations were much more prevalent in younger patients, which had a poor response to treatment with epidermal growth factor receptor kinase inhibitor. These results reveal a distinctive genetic profile in younger patients with adenocarcinoma, which might improve the treatment of this subpopulation.

Ribonucleotide reductase M2B inhibits cell migration and spreading by early growth response protein 1-mediated phosphatase and tensin homolog/Akt1 pathway in hepatocellular carcinoma.

UNLABELLED: Ribonucleotide reductase (RR)M2B is an enzyme belonging to the ribonucleotide reductase enzyme family, which is essential for DNA synthesis and repair. RRM2B plays an important role in tumor progression and metastasis; however, little is known about the expression and underlying molecular mechanisms of RRM2B in hepatocellular carcinoma (HCC). In the present study, we report that down-regulation of RRM2B in HCC is negatively associated with intrahepatic metastasis, regardless of p53 status. Moreover, the ectopic overexpression of RRM2B decreased HCC cell migration and invasion in vitro, whereas silencing RRM2B expression resulted in increased migration and invasion in vitro and intrahepatic and lung metastasis in vivo. Additionally, knockdown of RRM2B by short hairpin RNA (shRNA) in HCC cells was associated with epithelial-mesenchymal transition (EMT), including the down-regulation of E-cadherin, and the concomitant up-regulation of N-cadherin and slug. A further experiment showed that RRM2B inhibited cell migration and spreading through regulation of the early growth response protein 1 (Egr-1)/phosphatase and tensin homolog (PTEN)/Akt1 pathway. Consistently, we also detected a significant correlation between RRM2B and E-cadherin protein expression in HCC tissues. Furthermore, Egr-1 also directly bound to the RRM2B promoter and repressed RRM2B transcription, thereby establishing a negative regulatory feedback loop. CONCLUSION: These findings indicate that RRM2B suppresses cell migration and spreading by way of modulation of the Egr-1/PTEN/Akt1 pathway.

Case report: A rare immune-related adverse effect: hepatic cavernous hemangioma induced by camrelizumab.

Background: Camrelizumab, a programmed death 1 (PD-1) inhibiting antibody, has demonstrated efficacy in various malignancies and received approval in multiple countries. Despite its therapeutic benefits, camrelizumab is associated with a unique spectrum of immune-related adverse effects (irAEs), predominantly reactive cutaneous capillary endothelial proliferation (RCCEP). However, visceral manifestations of such endothelial proliferations, particularly hepatic cavernous hemangiomas, have not been extensively documented. Methods: This case series retrospectively reviews six patients who developed hepatic hemangiomas following treatment with camrelizumab in combination with other chemotherapeutic agents. The series highlights the clinical course, imaging findings, management strategies, and outcomes associated with this complication. A detailed analysis was conducted to discern the potential causal relationship between camrelizumab therapy and the development of hepatic hemangiomas. Results: All six patients, after varying cycles of camrelizumab-based therapy, presented with hepatic lesions identified as cavernous hemangiomas on imaging. These findings were atypical for metastatic disease and were further complicated by significant clinical events, including massive intra-abdominal bleeding post-biopsy. Discontinuation of camrelizumab led to a reduction in the size of the hemangiomas in two cases, suggesting a potential link between the drug and the development of these vascular lesions. The incidence of RCCEP remained high, and the use of other agents such as bevacizumab did not mitigate the occurrence of hepatic hemangiomas, indicating a possible unique pathogenic mechanism associated with camrelizumab. Conclusion: Hepatic cavernous hemangioma may represent a rare but clinically significant irAE associated with camrelizumab therapy. This series underscores the importance of vigilant monitoring and a high index of suspicion for atypical hepatic lesions in patients undergoing treatment with PD-1 inhibitors. Further studies are warranted to elucidate the pathophysiology of this complication and to establish guidelines for the management and surveillance of patients receiving camrelizumab.

Efficacy of immunotherapy in ARID1A-mutant solid tumors: a single-center retrospective study.

BACKGROUND: Immune checkpoint inhibitors (ICIs), especially those targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), have introduced a new treatment landscape for many types of tumors. However, they only achieve a limited therapeutic response. Hence, identifying patients who may benefit from ICIs is currently a challenge. METHODS: 47 tumor patients harboring ARID1A mutations were retrospectively studied. The genomic profiling data through next-generation sequencing (NGS) and relevant clinical information were collected and analyzed. Additionally, bioinformatics analysis of the expression of immune checkpoints and immune cell infiltration levels was conducted in ARID1A-mutant gastric cancer (GC). RESULTS: ARID1A mutations frequently co-occur with mutations in DNA damage repair (DDR)-associated genes. Among the 35 ARID1A-mutant patients who received immunotherapy, 27 were evaluable., with the objective response rate (ORR) was 48.15% (13/27), and the disease control rate (DCR) was 92.59% (25/27). Moreover, survival assays revealed that ARID1A-mutant patients had longer median overall survival (mOS) after immunotherapy. In ARID1A-mutated GC patients, receiving ICIs treatment indicated longer progressive-free survival (PFS). Additionally, the incidence of microsatellite instability-high (MSI-H), high tumor mutation burden (TMB-H) and Epstein‒Barr virus (EBV) infection was elevated. Bioinformatic analysis showed significant enrichment of immune response and T cell activation pathway within differentially expressed genes in ARID1A-mutant GC group. Finally, ARID1A mutations status was considered to be highly correlated with the level of tumor infiltrating lymphocytes (TILs) and high expression of immune checkpoints. CONCLUSIONS: Patients with tumors harboring ARID1A mutations may achieve better clinical outcomes from immunotherapy, especially in GC. ARID1A mutations can lead to genomic instability and reshape the tumor immune microenvironment (TIME), which can be used as a biomarker for immunotherapy.

Role of YES1 signaling in tumor therapy resistance.

YES proto-oncogene 1 (YES1) is an SRC family kinase (SFK) that plays a key role in cancer cell proliferation, adhesion, invasion, survival, and angiogenesis during tumorigenesis and tumor development. Reports suggest that YES1 amplification is associated with resistance to chemotherapeutic drugs and tyrosine kinase inhibitors (TKIs) in human malignancies. However, the mechanisms of drug resistance have not been fully elucidated. In this article, we review the literature on YES1 and discuss the implications of YES1 signaling for targeted therapy and chemotherapy resistance in malignancies. Moreover, recent advances in targeted therapy for YES1-amplified malignancies are summarized. Finally, we conclude that targeting YES1 may reverse drug resistance and serve as a valuable tumor treatment strategy.