Improved production of class I phosphatidylinositol 4,5-bisphosphate 3-kinase.

Phosphatidylinositol 4,5-bisphosphate 3-kinases (PI3K) are a family of kinases whose activity affects pathways needed for basic cell functions. As a result, PI3K is one of the most mutated genes in all human cancers and serves as an ideal therapeutic target for cancer treatment. Expanding on work done by other groups we improved protein yield to produce stable and pure protein using a variety of modifications including improved solubility tag, novel expression modalities, and optimized purification protocol and buffer. By these means, we achieved a 40-fold increase in yield for p110α/p85α and a 3-fold increase in p110α. We also used these protocols to produce comparable constructs of the ß and δ isoforms of PI3K. Increased yield enhanced the efficiency of our downstream high throughput drug discovery efforts on the PIK3 family of kinases.

Prediction of Kirsten rat sarcoma (KRAS) mutation in rectal cancer with amide proton transfer-weighted magnetic resonance imaging.

Background: Kirsten rat sarcoma (KRAS) mutation drives resistance to anti-epidermal growth factor receptor (anti-EGFR)-targeted therapies in rectal cancer. Amide proton transfer-weighted magnetic resonance imaging (APTw MRI) might be a supplement to the evaluation of KRAS mutation because the APTw value can reflect mobile cellular protein content in vivo. This study aimed to determine whether APTw MRI could predict KRAS mutation in rectal cancer and compare this technique with diffusion-weighted imaging (DWI). Methods: This retrospective study reviewed 153 consecutive patients with rectal cancer from April 2019 to June 2021 in our hospital. Among them, a total of 55 patients who did not undergo neoadjuvant chemoradiotherapy and underwent preoperative APTw MRI, DWI, and postoperative KRAS tests were included in this study. In two-dimensional APTw images, two radiologists manually delineated three regions of interest (ROIs) along tumor contour in the largest slice and the adjacent two slices of tumor respectively. The mean APTw value within a ROI was calculated, and the values of three ROIs were averaged for each patient. In consecutive DWI images, two radiologists depicted the ROIs of the whole lesion, and the mean apparent diffusion coefficient (ADC) was generated. The intraclass correlation coefficient (ICC), Shapiro-Wilk test and Student's t-test were used for statistical analyses. Receiver operating characteristic (ROC) curves were constructed for APTw and ADC values respectively, and the area under the curve (AUC) was used to evaluate the diagnostic performance for the prediction of KRAS mutation. Results: Among these 55 patients, KRAS mutation occurred in 21 patients. The ICCs of two independent raters for APTw and ADC values were 0.937 [95% confidence interval (CI), 0.914-0.953] and 0.976 (95% CI, 0.959-0.986), respectively. ADC values did not show a statistically significant difference between the KRAS-mutant group and the wild type (WT) group (P=0.733). KRAS-mutant tumors exhibited a higher APTw value than WT tumors in patients with rectal non-mucinous adenocarcinoma (3.324%±0.685% vs. 2.230%±0.833%, P<0.001). The AUC of the APTw value was 0.827 (95% CI, 0.701-0.916), with a cutoff value of 2.4% (sensitivity, 95.2%; specificity, 55.9%). Conclusions: DWI cannot differentiate mutant KRAS genes from WT genes in patients with rectal cancer, but APTw MRI has potential for evaluating KRAS mutation in rectal cancer. The APTw value had moderate diagnostic performance in the prediction of KRAS mutation with a high sensitivity but a low specificity. APTw MRI might be a promising supplement to KRAS genomic analysis in rectal cancer patients.

Successful treatment of GEMOX regimen combined with nimotuzumab in the pancreatic cancer with wild KRAS and mutant BRCA: a report of two cases.

Background: Pancreatic cancer is characterized by chemoresistance. In recent years, more potential therapeutic molecular targets for pancreatic cancer have been developed, and thus increasing attention has been paid to precise chemotherapy to improve the prognosis of patients with advanced pancreatic cancer. Case Description: In this study, we reported two rare cases of advanced pancreatic cancer. One patient was diagnosed with retroperitoneal lymph node metastasis after radical resection of pancreatic ductal adenocarcinoma. The diagnosis of another patient was pancreatic ductal adenocarcinoma with liver metastasis. The whole genome sequencing of their tumor tissues detected both wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) and mutant breast cancer susceptibility gene (BRCA). And immunohistochemistry showed their tumor tissue was negative for epidermal growth factor receptor. We used the combined chemotherapy of gemcitabine (1,000 mg/m2) + oxaliplatin (135 mg/m2) + nimotuzumab (400 mg). After nine times of chemotherapy, the imaging examinations including positron emission tomography-computed tomography showed that both cases achieved complete remission. And there were no serious side effects during chemotherapy. Then, the patients were treated with oral olaparide (600 mg/day) for one year, and survived without tumor progress for more than 1.5 years. Conclusions: These two cases achieved excellent effects of precise chemotherapy, which provided an important reference for the treatment of pancreatic cancer patients with wild KRAS and mutant BRCA.

Efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer patients with rare KRAS mutations: a real-world retrospective study.

Background: Kirsten rat sarcoma homolog (KRAS) mutations are one of the key drivers in non-small cell lung cancer (NSCLC) and FDA-approved specific inhibitors of KRAS-G12C mutation are available clinically. However, inhibitors of certain KRAS mutation subtypes remain unavailable, especially rare KRAS mutations including G13C, G13D, and Q61H. In this study, we retrospectively investigated the outcomes of NSCLC patients with rare KRAS-mutation to determine if they may benefit from immune checkpoint inhibitors (ICIs). Methods: Our retrospective study involved 240 advanced NSCLC patients with KRAS mutations, who visited Shanghai Chest Hospital from July 2018 to July 2021. Complete clinical and pathological data were recorded and progression-free survival (PFS) and overall survival (OS) were adopted as primary endpoints. Results: The median follow-up time was 36.5 months (range, 30.8-42.1 months) and the median OS was 9.7 months (range, 7.6-11.8 months). Of the 240 patients evaluated, 130 (54.2%) received chemotherapy and 110 (45.8%) received ICI-based treatment. Among the patients who received chemotherapy, patients with rare KRAS-mutations presented worse survival outcomes (median PFS, 3.4 vs. 4.1 months, P=0.047; median OS, 5.2 vs. 7.1 months, P=0.02) than conventional KRAS-mutant patients. PFS and OS of rare KRAS-mutation patients were prolonged after immunotherapy (median PFS 7.3 vs. 3.4 months, P<0.001; median OS, 13.3 vs. 5.2 months, P<0.001) and had no significant difference compared with conventional KRAS-mutant patients, in part of them whose programmed death-ligand 1 (PD-L1) expression data before immunotherapy were available (n=72), patients with a higher rate of PD-L1 positive tumor cells (≥50%) presented elevated PFS and OS. Conclusions: Despite having potential survival disadvantage compared with other NSCLC patients, rare KRAS-mutant patients (other than G12A, C, D, V) could benefit specifically from ICI-based therapy and survival outcomes are correlated with PD-L1 expression.

Clinical impact of EGFR and KRAS mutations in surgically treated unifocal and multifocal lung adenocarcinoma.

Background: Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (KRAS) are the two most common oncogenic drivers in lung adenocarcinoma, and their roles still need further exploration. Here we aimed to compare the clinical impact of EGFR and KRAS mutations on disease progression in resected unifocal and multifocal lung adenocarcinoma. Methods: Clinicopathologic and genomic data were collected for patients who underwent resection of lung adenocarcinoma from 2008 to 2022 at Stanford University Hospital. Retrospective review was performed in 241 patients whose tumors harbored EGFR (n=150, 62.2%) or KRAS (n=91, 37.8%) mutations. Clinical outcome was analyzed with special attention to the natural history of secondary nodules in multifocal cases wherein the dominant tumor had been resected. Results: We confirm that compared with EGFR mutations, patients with KRAS mutations had more smokers, larger tumor size, higher TNM stage, higher positron emission tomography (PET)/computed tomography (CT) standard uptake value max, higher tumor mutation burden, and worse disease-free survival and overall survival on univariate analysis. For patients with multifocal pulmonary nodules, the median follow-up of unresected secondary nodules was 55 months. Secondary nodule progression-free survival (SNPFS) was significantly worse for patients with KRAS mutations than those with EGFR mutations (mean 40.3±6.6 vs. 67.7±6.5 months, P=0.004). Univariate analysis showed tumor size, tumor morphology, pathologic TNM stage, and KRAS mutations were significantly associated with SNPFS, while multivariate analysis showed only KRAS mutations were independently associated with worse SNPFS (hazard ratio 1.752, 95% confidence interval: 1.017-3.018, P=0.043). Conclusions: Resected lung adenocarcinomas with KRAS mutations have more aggressive clinicopathological features and confer worse prognosis than those with EGFR mutations. Secondary pulmonary nodules in multifocal cases with dominant KRAS-mutant tumors have more rapid progression of the secondary nodules.

Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer.

More than 1.9 million new colorectal cancer (CRC) cases and 935000 deaths were estimated to occur worldwide in 2020, representing about one in ten cancer cases and deaths. Overall, colorectal ranks third in incidence, but second in mortality. More than half of the patients are in advanced stages at diagnosis. Treatment options are complex because of the heterogeneity of the patient population, including different molecular subtypes. Treatments have included conventional fluorouracil-based chemotherapy, targeted therapy, immunotherapy, etc. In recent years, with the development of genetic testing technology, more and more targeted drugs have been applied to the treatment of CRC, which has further prolonged the survival of metastatic CRC patients.

Development of PROTACS degrading KRAS and SOS1.

The Kirsten rat sarcoma virus-son of sevenless 1 (KRAS-SOS1) axis drives tumor growth preferentially in pancreatic, colon, and lung cancer. Now, KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of KRAS. However, the range of other KRAS mutations is not amenable to treatment and the G12C-directed agents Sotorasib and Adragrasib show a response rate of only approximately 40%, lasting for a mean period of 8 months. One approach to increase the efficacy of inhibitors is their inclusion into proteolysis-targeting chimeras (PROTACs), which degrade the proteins of interest and exhibit much higher antitumor activity through multiple cycles of activity. Accordingly, PROTACs have been developed based on KRAS- or SOS1-directed inhibitors coupled to either von Hippel-Lindau (VHL) or Cereblon (CRBN) ligands that invoke the proteasomal degradation. Several of these PROTACs show increased activity in vitro and in vivo compared to their cognate inhibitors but their toxicity in normal tissues is not clear. The CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental animals. Resistance to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin ligase. Although highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.

Targeting WEE1 enhances the antitumor effect of KRAS-mutated non-small cell lung cancer harboring TP53 mutations.

The clinical development of Kirsten rat sarcoma virus (KRAS)-G12C inhibitors for the treatment of KRAS-mutant lung cancer is limited by the presence of co-mutations, intrinsic resistance, and the emergence of acquired resistance. Therefore, innovative strategies for enhancing apoptosis in KRAS-mutated non-small cell lung cancer (NSCLC) are urgently needed. Through CRISPR-Cas9 knockout screening using a library of 746 crRNAs and drug screening with a custom library of 432 compounds, we discover that WEE1 kinase inhibitors are potent enhancers of apoptosis, particularly in KRAS-mutant NSCLC cells harboring TP53 mutations. Mechanistically, WEE1 inhibition promotes G2/M transition and reduces checkpoint kinase 2 (CHK2) and Rad51 expression in the DNA damage response (DDR) pathway, which is associated with apoptosis and the repair of DNA double-strand breaks, leading to mitotic catastrophe. Notably, the combined inhibition of KRAS-G12C and WEE1 consistently suppresses tumor growth. Our results suggest targeting WEE1 as a promising therapeutic strategy for KRAS-mutated NSCLC with TP53 mutations.

Advances in Systemic Therapy in Pancreatic Cancer.

Substantial progress has been made toward understanding biology and developing new therapies for pancreatic ductal adenocarcinoma (PDAC). In this review, new insights from genomic profiling, as well as implications for treatment and prognosis, are discussed. New standards of care approaches with a focus on drug therapies are discussed for the treatment of resectable and advanced PDAC. The role of targeted and immune therapies remains limited; cohorts likely to benefit from these approaches are discussed. Promising, preliminary results regarding experimental therapies are reviewed.

Multisequence MRI-based radiomics signature as potential biomarkers for differentiating KRAS mutations in non-small cell lung cancer with brain metastases.

Background: Kirsten rat sarcoma virus (KRAS) has evolved from a genotype with predictive value to a therapeutic target recently. The study aimed to establish non-invasive radiomics models based on MRI to discriminate KRAS from epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations in lung cancer patients with brain metastases (BM), then further explore the optimal sequence for prediction. Methods: This retrospective study involved 317 patients (218 patients in training cohort and 99 patients in testing cohort) who had confirmed of KRAS, EGFR or ALK mutations. Radiomics features were separately extracted from T2WI, T2 fluid-attenuated inversion recovery (T2-FLAIR), diffusion weighted imaging (DWI) and contrast-enhanced T1-weighted imaging (T1-CE) sequences. The maximal information coefficient and recursive feature elimination method were used to select informative features. Then we built four radiomics models for differentiating KRAS from EGFR or ALK using random forest classifier. ROC curves were used to validate the capability of the models. Results: The four radiomics models for discriminating KRAS from EGFR all worked well, especially DWI and T2WI models (AUCs: 0.942, 0.942 in training cohort, 0.949, 0.954 in testing cohort). When KRAS compared to ALK, DWI and T2-FLAIR models showed excellent performance in two cohorts (AUCs: 0.947, 0.917 in training cohort, 0.850, 0.824 in testing cohort). Conclusions: Radiomics classifiers integrating MRI have potential to discriminate KRAS from EGFR or ALK, which are helpful to guide treatment and facilitate the discovery of new approaches capable of achieving this long-sought goal of cure in lung cancer patients with KRAS.

Classical prescription Floris Sophorae Powder treat colorectal cancer by regulating KRAS/MEK-ERK signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Colorectal cancer (CRC) belongs to the category of intestinal wind, anal ulcer, abdominal mass and other diseases in traditional Chinese medicine (TCM). Floris Sophorae Powder (F.S), is a classical prescription is recorded in Puji Benshi Fang for the treatment of intestinal carbuncle. It has been incorporated into the prescriptions for the treatment of intestinal diseases and achieved remarkable results in modern medicine. However, the mechanism of F.S in the treatment of colorectal cancer remains unclear and requires further study. AIM OF THE STUDY: To investigate F.S in treating CRC and clarify the underlying mechanism. MATERIALS AND METHODS: This study was based on Dextran Sulfate Sodium Salt (DSS) combined with Azoxymethane (AOM) induced CRC mouse model to clarify the pharmacological effects of F.S. The serum metabolomics was used to study the mechanism of action, and the chemical composition of F.S was found by UPLC-Q-TOF-MS. The rationality of serm metabolomics results was verified through the clinical target database of network pharmacology, and the upstream and downstream targets of related pathways were found. The mechanism pathway was verified by Western blot to clarify its mechanism of action. RESULTS: In vivo pharmacological experiments showed that F.S inhibited tumor growth and improved hematochezia. The vital signs of mice in the high-dose F.S group approached to those in the control group. A total of 43 differential metabolites were found to be significantly changed by serum metabolomics. F.S could modulate and recover most of the differential metabolites, which proved to be closely related to the KRAS/MEK-ERK signaling pathway. A total of 46 compounds in F.S were identified, and the rationality of serm metabolic pathway was verified by network pharmacology. Western blot results also verified that the expression of KRAS, E2F1, p-MEK and p-ERK were significantly decreased after F.S treatment. CONCLUSION: Classical prescription Floris Sophorae Powder treat colorectal cancer by regulating KRAS/MEK-ERK signaling pathway.

CT-based non-invasive identification of the most common gene mutation status in patients with non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) are mutually exclusive, and they are two important genes that are most prone to mutation in patients with non-small cell lung cancer. PURPOSE: This retrospective study investigated the ability of radiomics to predict the mutation status of EGFR and KRAS in patients with non-small cell lung cancer (NSCLC) and guide precision medicine. METHODS: Computed tomography images of 1045 NSCLC patients from five different institutions were collected, and 1204 imaging features were extracted. In the training set (EGFR: 678, KRAS: 246), Max-Relevance and Min-Redundancy and least absolute shrinkage and selection operator logistic regression were used to screen radiomics features. The combination of selected radiomics features and clinical factors was used to establish the combined models in identifying EGFR and KRAS mutation status, respectively, through stepwise logistic regression. Then, on two independent external validation sets (EGFR: 203/164, KRAS: 123/95), the performance of each model was evaluated separately, and then the overall performance of predicting the two mutation states was calculated. RESULTS: In the EGFR and KRAS groups, radiomics signatures comprised 14 and 10 radiomics features, respectively. They were mutually exclusive between the tumors with positive EGFR mutation and those with positive KRAS mutation in imaging phenotype. For the EGFR group, the area under the curve (AUC) of the combined model in the two validation sets was 0.871 (95% CI: 0.821-0.926) and 0.861 (95% CI: 0.802-0.911), respectively, whereas the AUC of the combined model in the two validation sets was 0.798 (95% CI: 0.739-0.850) and 0.778 (95% CI: 0.735-0.821), respectively, for the KRAS group. Considering both EGFR and KRAS, the overall precision, recall, and F1-score of the combined model in the two validation sets were 0.704, 0.844, and 0.768, as well as 0.754, 0.693, and 0.722, respectively. CONCLUSIONS: Our study demonstrates the potential of radiomics in the non-invasive identification of EGFR and KRAS mutation status, which may guide patients with non-small cell lung cancer to choose the most appropriate personalized treatment. This method can be used when biopsy will bring unacceptable risk to patients with NSCLC.

Case Report: Case series: association between blood concentration and side effects of sotorasib.

Introduction: Sotorasib is a crucial therapeutic agent for patients with non-small cell lung cancer (NSCLC) harboring the KRAS p.G12C mutation. Despite its efficacy, the relationship between blood sotorasib concentrations and side effects remains largely unexplored. Methods: This study enrolled five patients with KRAS p.G12C-positive NSCLC treated with sotorasib (LUMAKRAS® Tablets, Amgen, Japan) between July 2022 and February 2023 at Asahikawa Medical University Hospital. Blood sotorasib levels were monitored, and their association with adverse events was examined, with no adjustments made to drug dosages based on these levels. Results: Variable blood sotorasib levels were observed among the participants. Notably, one patient developed interstitial pneumonitis, although a definitive attribution to sotorasib was uncertain due to prior pembrolizumab treatment. The study revealed no consistent association between blood sotorasib levels and adverse events or therapeutic outcomes, with some patients experiencing severe side effects at higher concentrations, while others did not. Conclusion: Preliminary findings suggested that monitoring blood sotorasib levels may aid in anticipating adverse events in this small cohort. However, future studies with larger sample sizes and extended follow-up periods are required to validate these initial observations. Such studies could potentially offer insights into personalized dosing strategies, thereby mitigating adverse effects and enhance patient care for individuals with KRAS p.G12C-positive NSCLC.

Elevated FBXL6 activates both wild-type KRAS and mutant KRASG12D and drives HCC tumorigenesis via the ERK/mTOR/PRELID2/ROS axis in mice.

BACKGROUND: Kirsten rat sarcoma (KRAS) and mutant KRASG12D have been implicated in human cancers, but it remains unclear whether their activation requires ubiquitination. This study aimed to investigate whether and how F-box and leucine-rich repeat 6 (FBXL6) regulates KRAS and KRASG12D activity in hepatocellular carcinoma (HCC). METHODS: We constructed transgenic mouse strains LC (LSL-Fbxl6KI/+;Alb-Cre, n = 13), KC (LSL-KrasG12D/+;Alb-Cre, n = 10) and KLC (LSL-KrasG12D/+;LSL-Fbxl6KI/+;Alb-Cre, n = 12) mice, and then monitored HCC for 320 d. Multiomics approaches and pharmacological inhibitors were used to determine oncogenic signaling in the context of elevated FBXL6 and KRAS activation. Co­immunoprecipitation (Co-IP), Western blotting, ubiquitination assay and RAS activity detection assay were employed to investigate the underlying molecular mechanism by which FBXL6 activates KRAS. The pathological relevance of the FBXL6/KRAS/extracellular signal-regulated kinase (ERK)/mammalian target of rapamycin (mTOR)/proteins of relevant evolutionary and lymphoid interest domain 2 (PRELID2) axis was evaluated in 129 paired samples from HCC patients. RESULTS: FBXL6 is highly expressed in HCC as well as other human cancers (P < 0.001). Interestingly, FBXL6 drives HCC in transgenic mice. Mechanistically, elevated FBXL6 promotes the polyubiquitination of both wild-type KRAS and KRASG12D at lysine 128, leading to the activation of both KRAS and KRASG12D and promoting their binding to the serine/threonine-protein kinase RAF, which is followed by the activation of mitogen-activated protein kinase kinase (MEK)/ERK/mTOR signaling. The oncogenic activity of the MEK/ERK/mTOR axis relies on PRELID2, which induces reactive oxygen species (ROS) generation. Furthermore, hepatic FBXL6 upregulation facilitates KRASG12D to induce more severe hepatocarcinogenesis and lung metastasis via the MEK/ERK/mTOR/PRELID2/ROS axis. Dual inhibition of MEK and mTOR effectively suppresses tumor growth and metastasis in this subtype of cancer in vivo. In clinical samples, FBXL6 expression positively correlates with p-ERK (χ2 = 85.067, P < 0.001), p-mTOR (χ2 = 66.919, P < 0.001) and PRELID2 (χ2 = 20.891, P < 0.001). The Kaplan-Meier survival analyses suggested that HCC patients with high FBXL6/p-ERK levels predicted worse overall survival (log­rank P < 0.001). CONCLUSIONS: FBXL6 activates KRAS or KRASG12D via ubiquitination at the site K128, leading to activation of the ERK/mTOR/PRELID2/ROS axis and tumorigenesis. Dual inhibition of MEK and mTOR effectively protects against FBXL6- and KRASG12D-induced tumorigenesis, providing a potential therapeutic strategy to treat this aggressive subtype of liver cancer.

Clinical outcomes of KRAS-mutant non-small cell lung cancer under untargeted therapeutic regimes in the real world: a retrospective observational study.

Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation seemingly suffered less effective therapeutic regimens in the absence of widely-accepted targeted drugs compared with other mutation types in non-small cell lung cancer (NSCLC). However, whether these non-selective therapy schedules for KRAS mutation matters is still under debate. Correspondingly, we aimed to compare the long term expectancy of indicated therapeutic regimes and further explore the optimal schemes of KRAS mutated NSCLC in the absence of targeted drugs in this retrospective study cohort. Methods: We conducted a single-center retrospective analysis among 66 patients diagnosed with KRAS-mutant advanced NSCLC from November 2018 to December 2020. These enrolled cases were divided into different subgroups in light of mutant isotypes, pathological characteristics, and therapeutic regimes to uncover indicated long-term survival benefits. Additionally, clinical outcomes of treatment schedules and interventional lines to KRAS-mutant NSCLC were described in detail. Results: This cohort enrolled 8 patients with stage IIIB (12.1%) and 58 patients with stage IV (87.9%) with the median age 62 years, ranging from 32 to 91 years old. Genetically, G12C conducted as the most common KRAS mutation type, accounting for 30.3%. Pemetrexed combined with platinum chemotherapy seemed to be a priority (72.7%), and chemotherapy combined with immunotherapy became an alternative (15.2%) in clinic. Performing further analysis of long-term survival of patients receiving different treatment methods indicated that the median overall survival (mOS) in first-line therapy with antiangiogenesis or untreated was 13 and 12 months, respectively (P=0.79). In the first-line regimen, median survival was 17 months for patients who received combined immune checkpoint inhibitors and 12 months for those who did not (P=0.34). The mOS was 20 months for those who had used immune checkpoint inhibitors and 12 months for those who had not (P=0.11). Survival analysis results of NSCLC patients with different KRAS mutation types showed the median survival time of patients with G12C mutation type and patients without with nonG12C mutation type was 19 and 12 months, respectively (P=0.37). Conclusions: In the absence of KRAS targeted drugs, available treatment plans failed to benefit KRAS mutant sufferers regardless of isotypes, making the KRAS-targeted drugs urgent.

Integration of signaling pathway and bromodomain and extra-terminal domain inhibition for the treatment of mutant Kirsten rat sarcoma viral oncogene homolog cancer.

Mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) is now a drugable oncogenic driver and the KRAS G12C variant responds clinically to sotorasib and adagrasib that covalently block the cysteine of the active center and inhibit downstream signaling and proliferation. Unfortunately, progression-free survival (PFS) of lung cancer patients is only 5-6 months and no survival advantage has been found for sotorasib in comparison to docetaxel chemotherapy. Increased responses to KRAS inhibitors are tested in combination with the son of sevenless 1 (SOS1) inhibitors, upstream and downstream signaling modulators as well as chemotherapeutics. Some of these approaches are limited by toxicity to normal tissues and by diverse mechanisms of resistance. In essence, most of these attempts are directed to the inhibition of proliferation by impairment of the signal transduction pathways. The final target of KRAS-mediated growth stimulation is MYC in the cell nucleus that stimulates transcription of a host of genes. In detail, MYC alters genomic enhancer and super-enhancers of transcription that are frequently deregulated in cancer. Such enhancers can be targeted by bromodomain and extra-terminal (BET) inhibitors (BETi) or degraders and this review discusses whether integrated SOS1 inhibition and BET targeting of MYC synergizes against mutant KRAS tumor growth. BET degraders in the form of proteolysis-targeting chimeras (PROTACs) combined with BAY-293-mediated SOS1 inhibition revealed marked cytotoxic synergy against mutant KRAS cancer cells and may constitute a promising option for clinical treatment.