Evaluation of the prognostic value of the new 9th edition Tumor-Node-Metastases (TNM) staging system for epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma patients with bone metastases.

BACKGROUND: There are some changes in the new 9th edition Tumor-Node-Metastases (TNM) staging system for lung cancer, including subdividing M1c into M1c1 and M1c2 stage. The aim of this study was to assess the prognostic performance of the updated classification system and try to provide some real-world application data among advanced lung adenocarcinoma patients with bone metastases. METHODS: Advanced lung adenocarcinoma patients in M1c stage with bone metastases who receiving first-line first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and T790M-guided osimertinib as the second-line therapy were retrospectively screened from December 2016 to December 2021. A total of 126 patients were enrolled in this study. 62 patients and 64 patients were subdivided into M1c1 and M1c2 groups according to the 9th edition of TNM staging system.The first-line real-world progression-free survival (1LrwPFS), the second-line real-world progression-free survival (2LrwPFS), post-progression survival (PPS) and real-world overall survival (rwOS) were analyzed. RESULTS: The overall median rwOS was 40.1 months (95% CI 35.996-44.204). 1LrwPFS was 13.9 months (95% CI 12.653-15.147) and 2LrwPFS was 14.5 months (95% CI 11.665-17.335) for all patients.Patients in M1c2 stage was inferior to M1c1 stage patients in rwOS (35.2 months vs. 42.9 months, HR = 0.512, P = 0.005). 2LrwPFS was moderately correlated with rwOS (r = 0.621, R2 = 0.568, P = 0.000). Multivariate analysis showed performance status (PS) score ≥ 2 and TP53 alteration positive were independent prognostic factors of worse rwOS. CONCLUSIONS: More refined stratification of M1c according to the 9th edition of TNM staging system is conducive to the judgment of prognosis and the implementation of precision medicine for patients.

A comparative study of the efficacy and safety of PD-1/L1 inhibitor and platinum-containing dual-agent chemotherapy in patients with advanced non-small cell lung cancer resistant to EGFR-TKIs.

OBJECTIVE: To assess the efficacy and safety of combining Programmed Death-1/Programmed Death-Ligand 1 (PD-1/L1) inhibitors with platinum-containing chemotherapy for treating late-stage Non-Small Cell Lung Cancer (NSCLC) patients who have developed resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs). METHODS: A retrospective analysis was conducted at Baoji Traditional Chinese Medicine Hospital involving 133 patients with advanced NSCLC who had shown resistance to EGFR-TKIs and were treated from October 2018 to May 2021. The cohort was categorized into two groups: one treated with immune checkpoint inhibitors (ICIs) plus chemotherapy and antiangiogenic agents (ICIs+BCP group), and the other treated with ICIs alone (ICIs group). Baseline data collected included demographic factors, smoking status, PD-L1 Tumor Proportion Score (TPS), EGFR mutation, Eastern Cooperative Oncology Group (ECOG) score, and routine blood markers prior to second-line therapy. Computed Tomography (CT) scans were performed every two treatment courses to evaluate the treatment efficacy. RESULTS: The ICIs+BCP group exhibited a statistically significant improvement in Overall Survival (OS) compared to the ICIs group (P=0.001). Cox survival analysis uncovered age (P=0.012), PD-L1 TPS expression (P<0.001), treatment regimen (P=0.006), Neutrophil-to-Lymphocyte Ratio (NLR) (P=0.024), and Platelet-to-Lymphocyte Ratio (PLR) (P=0.005) as independent factors influencing OS in patients with advanced NSCLC resistant to primary-line EGFR-TKI therapy. The nomogram model, based on these prognostic factors, exhibited Area Under the Curve (AUC) values of 0.823 and 0.769, indicating its predictive accuracy for 1-year and 2-year survival, respectively. CONCLUSION: Combining ICIs with BCP prolongs OS in patients with NSCLC resistant to EGFR-TKIs. This study underscores the importance of personalized treatment plans and biomarker evaluations to improve outcomes in drug-resistant cases.

Conserved regulatory motifs in the juxtamembrane domain and kinase N-lobe revealed through deep mutational scanning of the MET receptor tyrosine kinase domain.

MET is a receptor tyrosine kinase (RTK) responsible for initiating signaling pathways involved in development and wound repair. MET activation relies on ligand binding to the extracellular receptor, which prompts dimerization, intracellular phosphorylation, and recruitment of associated signaling proteins. Mutations, which are predominantly observed clinically in the intracellular juxtamembrane and kinase domains, can disrupt typical MET regulatory mechanisms. Understanding how juxtamembrane variants, such as exon 14 skipping (METΔEx14), and rare kinase domain mutations can increase signaling, often leading to cancer, remains a challenge. Here, we perform a parallel deep mutational scan (DMS) of the MET intracellular kinase domain in two fusion protein backgrounds: wild-type and METΔEx14. Our comparative approach has revealed a critical hydrophobic interaction between a juxtamembrane segment and the kinase ⍺C-helix, pointing to potential differences in regulatory mechanisms between MET and other RTKs. Additionally, we have uncovered a ß5 motif that acts as a structural pivot for the kinase domain in MET and other TAM family of kinases. We also describe a number of previously unknown activating mutations, aiding the effort to annotate driver, passenger, and drug resistance mutations in the MET kinase domain.

Fibroblast Growth Factor 2 (FGF2) Activates Vascular Endothelial Growth Factor (VEGF) Signaling in Gastrointestinal Stromal Tumors (GIST): An Autocrine Mechanism Contributing to Imatinib Mesylate (IM) Resistance.

We showed previously that the autocrine activation of the FGFR-mediated pathway in GIST lacking secondary KIT mutations was a result of the inhibition of KIT signaling. We show here that the FGF2/FGFR pathway regulates VEGF-A/VEGFR signaling in IM-resistant GIST cells. Indeed, recombinant FGF2 increased the production of VEGF-A by IM-naive and resistant GIST cells. VEGF-A production was also increased in KIT-inhibited GIST, whereas the neutralization of FGF2 by anti-FGF2 mAb attenuated VEGFR signaling. Of note, BGJ 398, pan FGFR inhibitor, effectively and time-dependently inhibited VEGFR signaling in IM-resistant GIST T-1R cells, thereby revealing the regulatory role of the FGFR pathway in VEGFR signaling for this particular GIST cell line. This also resulted in significant synergy between BGJ 398 and VEGFR inhibitors (i.e., sunitinib and regorafenib) by enhancing their pro-apoptotic and anti-proliferative activities. The high potency of the combined use of VEGFR and FGFR inhibitors in IM-resistant GISTs was revealed by the impressive synergy scores observed for regorafenib or sunitinib and BGJ 398. Moreover, FGFR1/2 and VEGFR1/2 were co-localized in IM-resistant GIST T-1R cells, and the direct interaction between the aforementioned RTKs was confirmed by co-immunoprecipitation. In contrast, IM-resistant GIST 430 cells expressed lower basal levels of FGF2 and VEGF-A. Despite the increased expression VEGFR1 and FGFR1/2 in GIST 430 cells, these RTKs were not co-localized and co-immunoprecipitated. Moreover, no synergy between FGFR and VEGFR inhibitors was observed for the IM-resistant GIST 430 cell line. Collectively, the dual targeting of FGFR and VEGFR pathways in IM-resistant GISTs is not limited to the synergistic anti-angiogenic treatment effects. The dual inhibition of FGFR and VEGFR pathways in IM-resistant GISTs potentiates the proapoptotic and anti-proliferative activities of the corresponding RTKi. Mechanistically, the FGF2-induced activation of the FGFR pathway turns on VEGFR signaling via the overproduction of VEGF-A, induces the interaction between FGFR1/2 and VEGFR1, and thereby renders cancer cells highly sensitive to the dual inhibition of the aforementioned RTKs. Thus, our data uncovers the novel mechanism of the cross-talk between the aforementioned RTKs in IM-resistant GISTs lacking secondary KIT mutations and suggests that the dual blockade of FGFR and VEGFR signaling might be an effective treatment strategy for patients with GIST-acquired IM resistance via KIT-independent mechanisms.

AXL expression reflects tumor-immune cell dynamics impacting outcome in non-small cell lung cancer patients treated with immune checkpoint inhibitor monotherapy.

Introduction: AXL receptor expression is proposed to confer immune-checkpoint inhibitor (ICI)-resistance in non-small cell lung cancer (NSCLC) patients. We sought to interrogate AXL expression in conjunction with mutational and tumor-microenvironmental features to uncover predictive mechanisms of resistance in ICI-treated NSCLC patients. Methods: Tumor samples from 111 NSCLC patients treated with ICI-monotherapy were analyzed by immunohistochemistry for tumor- and immune-AXL expression. Subsets of patients were analyzed by whole-exome sequencing (n = 44) and imaging mass cytometry (n = 14). Results were related to ICI-outcome measurements. Results: Tumor-cell AXL expression correlated with aggressive phenotypic features including reduced OS in patients treated with ICIs (P = 0.04) after chemotherapy progression, but conversely associated with improved disease control (P = 0.045) in ICI-treated, PD-L1 high first-line patients. AXL+ immune-cell infiltration correlated with total immune-cell infiltration and improved overall outcomes (PFS: P = 0.044, OS: P = 0.054). Tumor-cell AXL-upregulation showed enrichment in mutations associated with PD-L1-upregulation and ICI-response such as MUC4 and ZNF469, as well as adverse mutations including CSMD1 and LRP1B which associated with an immune-suppressed tumor phenotype and poor ICI prognosis particularly within chemotherapy-treated patients. Tumor mutational burden had no effect on ICI-outcomes and was associated with a lack of tumor-infiltrating immune cells. Spatial-immunophenotyping provided evidence that tumor-cell AXL-upregulation and adverse mutations modulate the tumor microenvironment in favor of infiltrating, activated neutrophils over anti-tumor immune-subsets including CD4 and CD8 T-cells. Conclusion: Tumor-cell AXL-upregulation correlated with distinct oncotypes and microenvironmental immune-profiles that define chemotherapy-induced mechanisms of ICI-resistance, which suggests the combination of AXL inhibitors with current chemoimmunotherapy regimens can benefit NSCLC patients.

Receptor Pharmacogenomics: Deciphering Genetic Influence on Drug Response.

The paradigm "one drug fits all" or "one dose fits all" will soon be challenged by pharmacogenetics research and application. Drug response-efficacy or safety-depends on interindividual variability. The current clinical practice does not include genetic screening as a routine procedure and does not account for genetic variation. Patients with the same illness receive the same treatment, yielding different responses. Integrating pharmacogenomics in therapy would provide critical information about how a patient will respond to a certain drug. Worldwide, great efforts are being made to achieve a personalized therapy-based approach. Nevertheless, a global harmonized guideline is still needed. Plasma membrane proteins, like receptor tyrosine kinase (RTK) and G protein-coupled receptors (GPCRs), are ubiquitously expressed, being involved in a diverse array of physiopathological processes. Over 30% of drugs approved by the FDA target GPCRs, reflecting the importance of assessing the genetic variability among individuals who are treated with these drugs. Pharmacogenomics of transmembrane protein receptors is a dynamic field with profound implications for precision medicine. Understanding genetic variations in these receptors provides a framework for optimizing drug therapies, minimizing adverse reactions, and advancing the paradigm of personalized healthcare.

[Corrigendum] miR-382 inhibits migration and invasion by targeting ROR1 through regulating EMT in ovarian cancer.

Following the publication of the above article, an interested reader drew to the authors' attention that certain of the Transwell migration and invasion assay data panels shown in Figs. 3E and G and 7E and G on p. 1754 and 1757 respectively contained overlapping data panels, both within Fig. 3 and between Figs. 3 and 7, such that data which were intended to represent the results of differently performed experiments had apparently been derived from the same original sources. Specifically, the 'con' and 'pre-con' data panels in Fig. 3 were overlapping, as were the 'pre-con' and 'pcDNA.1-ROR1' panels comparing Fig. 3 with Fig. 7, and the Editorial Office subsequently pointed out to the authors that the 'con' and 'pre-con' data panels in Fig. 3E also contained an overlapping edge. After having examined their original data, the authors realized that these figures were inadvertently assembled incorrectly. The corrected versions of Figs. 3 and 7 are shown on the next page, now showing the correct data for the 'con' experiment in Fig. 3E, the 'pre-con' experiment in Fig. 3G, and the 'pcDNA.1-ROR1' panel in Fig. 7G. 'The authors are grateful to the Editor of International Journal of Oncology for granting them the opportunity to publish this corrigendum, and all the authors agree with its publication; furthermore, they apologize to the readership of the journal for any inconvenience caused. [International Journal of Oncology 48: 181-190, 2016; DOI: 10.3892/ijo.2015.3241].

Unveiling the therapeutic promise of EphA2 in glioblastoma: a comprehensive review.

Glioblastoma (GBM), a primary brain tumor, exhibits remarkable invasiveness and is characterized by its intricate location, infiltrative behavior, the presence of both the blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB), phenotypic diversity, an immunosuppressive microenvironment with limited development yet rich vascularity, as well as the resistant nature of glioblastoma stem cells (GSCs) towards traditional chemotherapy and radiotherapy. These formidable factors present substantial obstacles in the quest for effective GBM treatments. Following extensive research spanning three decades, the hepatocellular receptor A2 (EphA2) receptor tyrosine kinase has emerged as a promising molecular target with translational potential in the realm of cancer therapy. Numerous compounds aimed at targeting EphA2 have undergone rigorous evaluation and clinical investigation. This article provides a comprehensive account of the distinctive roles played by canonical and non-canonical EphA2 signaling in various contexts, while also exploring the involvement of the EphA2-ephrin A1 signaling axis in GBM pathogenesis. Additionally, the review offers an overview of completed clinical trials targeting EphA2 for GBM treatment, shedding light on both the prospects and challenges associated with EphA2-directed interventions in the domain of cancer therapeutics.

High NTRK2 protein expression levels may be associated with poorer prognosis of breast cancer patients.

OBJECTIVE: Previous research has shown that the role of neurotrophic receptor tyrosine kinase 2 (NTRK2) in breast cancer (BRCA) remains ambiguous. To help elucidate this, we conducted a retrospective study to investigate the relationship between NTRK2 protein expression and BRCA. METHODS: The prognostic significance of NTRK2 protein expression patterns was assessed by performing immunohistochemistry assays on 131 BRCA tissues and 56 adjacent normal tissues in a retrospective study. Furthermore, the sensitivity to chemotherapeutic drugs was quantified by "pRRophetic" and the sensitivity to immunotherapy was estimated using The Cancer Immunome Atlas website. RESULTS: NTRK2 protein was expressed at significantly higher levels in BRCA samples compared with normal tissues. The data indicated that NTRK2 expression is an independent risk factor for BRCA patient prognosis. Additionally, the high NTRK2 group exhibited increased sensitivity to certain chemotherapy drugs and achieved higher scores for immune checkpoint blockade therapy compared with the low NTRK2 group. CONCLUSIONS: Our study demonstrated that higher NTRK2 protein expression is related to a less favorable prognosis in BRCA patients, as well as to enhanced sensitivity to specific chemotherapy and immunotherapy drugs.

DDR1 is a Novel Biomarker and Potential Therapeutic Target for the Combination Treatment of Liver Hepatocellular Carcinoma.

AIM: This study aimed to investigate the role of discoidin domain receptor tyrosine kinase 1 (DDR1) in liver hepatocellular carcinoma (LIHC) and to evaluate its prognostic value on patient response to combination therapy. METHODS: In the current retrospective study, we examined the protein expression of DDR1 in various cancers by standard immunohistochemical (IHC) methods and evaluated its clinical significance in LIHC personalized treatment. Multiple online databases, including The Cancer Genome Atlas (TCGA), TIMER, GEO, ROC Plotter, and Genomics of Drug Sensitivity in Cancer (GDSC), were used. RESULTS: DDR1 protein expression was higher in LIHC than in other nine examined cancer types. Additionally, DDR1 exhibited higher expression levels in adjacent normal tissues compared to HBs-positive LIHC tissues. Analysis at single-cell resolution revealed that DDR1 was expressed primarily in epithelial cells but not in stromal and immune cells, and DDR1 expression was lower in HBs-positive LIHC cells in comparison with normal hepatocytes. Correlation of DDR1 upregulation and sorafenib resistance was observed in the patient cohort. Moreover, DDR1 expression positively correlated with the expression of inflammatory response-related genes, ECM-related genes, and collagen formation-related genes, but negatively correlated with the infiltration of CD8+ T cells, NK cells, and dendritic cells in LIHC. CONCLUSIONS: Our findings suggest that DDR1 expression might be induced by collagen production-related cellular events involved in liver injury and repair, and that DDR1 overexpression might contribute to the resistance to LIHC targeted therapy and immunotherapy, highlighting DDR1 as a potential prognostic biomarker and therapeutic target.

This study aimed to investigate the role of discoidin domain receptor tyrosine kinase 1 (DDR1) in liver hepatocellular carcinoma (LIHC) and to evaluate its prognostic value on patient response to combination therapy. In the current retrospective study, we examined the protein expression of DDR1 in various cancers by standard immunohistochemical (IHC) methods and evaluated its clinical significance in LIHC personalized treatment. Multiple online databases, including The Cancer Genome Atlas (TCGA), TIMER, GEO, ROC Plotter, and Genomics of Drug Sensitivity in Cancer (GDSC), were used. DDR1 protein expression was higher in LIHC than in other nine examined cancer types. Additionally, DDR1 exhibited higher expression levels in adjacent normal tissues compared to HBs-positive LIHC tissues. Analysis at single-cell resolution revealed that DDR1 was expressed primarily in epithelial cells but not stromal cells and immune cells, and DDR1 expression was lower in HBs-positive LIHC cells in comparison with normal hepatocytes. Correlation of DDR1 upregulation and sorafenib resistance was observed in patient cohort. Moreover, DDR1 expression positively correlated with the expression of inflammatory response-related genes, ECM-related genes, and collagen formation-related genes but negatively correlated with the infiltration of CD8 + T cells, NK cells, and dendritic cells in LIHC. Our findings suggest that DDR1 expression might be induced by collagen production-related cellular events involved in liver injury and repair and that DDR1 overexpression might contribute to the resistance to LIHC targeted therapy and immunotherapy, highlighting DDR1 as a potential prognostic biomarker and therapeutic target.

Advancements in understanding cardiotoxicity of EGFR- TKIs in non-small cell lung cancer treatment and beyond.

Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) are a class of oral targeted anticancer drugs that have been demonstrated to significantly inhibit tumor progression and improve clinical prognosis in patients diagnosed with EGFR-mutated tumors, particularly in those with non-small cell lung cancer. However, the sustained usage of EGFR-TKIs may cause potential cardiotoxicity, thus limiting their applicability. The primary objective of this review is to systematically analyze the evolving landscape of research pertaining to EGFR-TKI-induced cardiotoxicity and elucidate its underlying mechanisms, such as PI3K signaling pathway inhibition, ion channel blockade, oxidative stress, inflammatory responses, and apoptosis. Additionally, the review includes an exploration of risk assessment for cardiotoxicity induced by EGFR-TKIs, along with management and response strategies. Prospective research directions are outlined, emphasizing the need for more accurate predictors of cardiotoxicity and the development of innovative intervention strategies. In summation, this review consolidates recent research advances, illuminates the risks associated with EGFR-TKI-induced cardiac toxicity and presents crucial insights for refining clinical dosage protocols, optimizing patient management strategies, and unraveling the intricate mechanisms governing EGFR-TKI-induced cardiotoxicity.

Receptor Tyrosine Kinase Signaling Involves Echinococcus-Host Intercommunication: A Potential Therapeutic Target in Hepatic Echinococcosis.

Echinococcosis, one of the most serious and life-threatening parasitic forms of zoonosis worldwide, is caused by the larvae of Echinococcus granulosus (E. granulosus) and Echinococcus multilocularis (E. multilocularis). Various drugs are being applied clinically to treat zoonosis; however, their therapeutic efficacy remains a great challenge, especially with albendazole as the preferred drug of choice. Receptor tyrosine kinase (RTK) signaling controls normal cellular proliferation, differentiation, and metabolism in humans and mammals, which are intermediate hosts of E. granulosus and E. multilocularis. Disruption of RTK signaling can cause various forms of carcinogenesis and exacerbate the progression of certain forms of parasitic disease. As a result, a significant number of studies on tyrosine kinase inhibitors (TKIs) have been conducted for the treatment of cancer and parasitic infection, with some TKIs already approved for clinical use for cancer. Notably, RTK signaling has been identified in the parasites E. granulosus and E. multilocularis; however, the mechanisms of RTK signaling response in Echinococcus-host intercommunication are not fully understood. Thus, understanding the RTK signaling response in Echinococcus-host intercommunication and the potential effect of RTK signaling is crucial for identifying new drug targets for echinococcosis. The present review illustrates that RTK signaling in the host is over-activated following infection by E. granulosus or E. multilocularis and can further facilitate the development of metacestodes in vitro. In addition, some TKIs exert strong parasitostatic effects on E. granulosus or E. multilocularis, both in vitro and/or in vivo, through downregulation of RTK signaling molecules. The summarized findings suggest that RTK signaling may be a promising drug target and that TKIs could be potential anti-Echinococcus drugs warranting further research.

LncRNA MALAT-1 modulates EGFR-TKI resistance in lung adenocarcinoma cells by downregulating miR-125.

Molecular targeted therapy resistance remains a major challenge in treating lung adenocarcinoma (LUAD). The resistance of Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs, epidermal growth factor receptor-tyrosine kinase inhibitor) plays a dominant role in molecular targeted therapy. Our previous research demonstrated the role of MALAT-1 (Metastasis-associated lung adenocarcinoma transcript 1) in the formation of Erlotinib-resistant LUAD cells. This study aims to uncover the mechanism of MALAT-1 overexpression in Erlotinib-resistant LUAD cells. The RT2 LncRNA PCR array system was used to explore MALAT-1 regulation in Erlotinib-resistant LUAD cells through patient serum analysis. Dual luciferase reporter experiments confirmed the binding between MALAT-1 and miR-125, leading to regulation of miR-125 expression. Functional assays were performed to elucidate the impact of MALAT1 on modulating drug resistance, growth, and Epithelial-mesenchymal transition (EMT, Epithelial-mesenchymal transition) in both parental and Erlotinib-resistant LUAD cells. The investigation unveiled the mechanism underlying the competing endogenous RNA (ceRNA, competing endogenouse RNA) pathway. MALAT1 exerted its regulatory effect on miR-125 as a competing endogenous RNA (ceRNA). Moreover, MALAT1 played a role in modulating the sensitivity of LUAD cells to Erlotinib. Rab25 was identified as the direct target of miR-125 and mediated the functional effects of MALAT1 in Erlotinib-resistant LUAD cells. In conclusion, our study reveals overexpress MALAT-1 cause the drug resistance of EGFR-TKIs in non-small cell lung cancer (NSCLC) through the MALAT-1/miR-125/Rab25 axis. These findings present a potential novel therapeutic target and perspective for the treatment of LUAD.

The Caenorhabditis elegans protein SOC-3 permits an alternative mode of signal transduction by the EGL-15 FGF receptor.

Fibroblast Growth Factors and their receptors (FGFRs) comprise a cell signaling module that can stimulate signaling by Ras and the kinases Raf, MEK, and ERK to regulate animal development and homeostatic functions. In Caenorhabditis elegans, the sole FGFR ortholog EGL-15 acts with the GRB2 ortholog SEM-5 to promote chemoattraction and migration by the sex myoblasts (SMs) and fluid homeostasis by the hypodermis (Hyp7). Cell-specific differences in EGL-15 signaling were suggested by the phenotypes caused by egl-15(n1457), an allele that removes a region of its C-terminal domain (CTD) known to bind SEM-5. To determine how mutations altered EGL-15 activity in the SMs and Hyp7, we used the kinase reporter ERK-KTR to measure activation of the ERK ortholog MPK-1. Consequences of egl-15(n1457) were cell-specific, resulting in loss of MPK-1 activity in the SMs and elevated activity in Hyp7. Previous studies of Hyp7 showed that loss of the CLR-1 phosphatase causes a fluid homeostasis defect termed "Clear" that is suppressed by reduction of EGL-15 signaling, a phenotype termed "Suppressor of Clear" (Soc). To identify mechanisms that permit EGL-15 signaling in Hyp7, we conducted a genetic screen for Soc mutants in the clr-1; egl-15(n1457) genotype. We report the identification of SOC-3, a protein with putative SEM-5-binding motifs and PH and PTB domains similar to DOK and IRS proteins. In combination with the egl-15(n1457) mutation, loss of either soc-3, the GAB1 ortholog soc-1, or the SHP2 ortholog ptp-2, reduced MPK-1 activation. We generated alleles of soc-3 to test the requirement for the SEM-5-binding motifs, finding that residue Tyr356 is required for function. We propose that EGL-15-mediated SM chemoattraction relies solely on the direct interaction between SEM-5 and the EGL-15 CTD. In Hyp7, EGL-15 signaling uses two mechanisms: the direct SEM-5 binding mechanism; and an alternative, CTD-independent mechanism involving SOC-3, SOC-1, and PTP-2. This work demonstrates that FGF signaling uses distinct, tissue-specific mechanisms in development, and identifies SOC-3 as a potential adaptor that facilitates Ras pathway activation by FGFR.

Immunohistochemistry Screening of Different Tyrosine Kinase Receptors in Canine Solid Tumors-Part I: Proposal of a Receptor Panel to Predict Therapies.

The use of tyrosine kinase inhibitors (TKI) has been growing in veterinary oncology and in the past few years several TKI have been tested in dogs. However, different from human medicine, we lack strategies to select patients to be treated with each TKI. Therefore, this study aimed to screen different tumor subtypes regarding TKI target immunoexpression as a predictor strategy to personalize the canine cancer treatment. It included 18 prostatic carcinomas, 36 soft tissue sarcomas, 20 mammary gland tumors, 6 urothelial bladder carcinomas, and 7 tumors from the endocrine system. A total of 87 patients with paraffin blocks were used to perform immunohistochemistry (IHC) of human epidermal growth factor receptor 2 (HER-2), epidermal growth factor receptors 1 (EGFR1), vascular endothelial growth factor receptor 2 (VEGFR-2), platelet derived growth factor receptor beta (PDGFR-ß), c-KIT, and extracellular signal-regulated kinase 1/2 (ERK1/ERK2). The immunohistochemical screening revealed a heterogeneous protein expression among histological types with mesenchymal tumors showing the lowest expression level and carcinomas the highest expression. We have demonstrated by IHC screening that HER2, EGFR1, VEGFR-2, PDGFR-ß and ERK1/ERK2 are commonly overexpressed in dogs with different carcinomas, and KIT expression is considered relatively low in the analyzed samples.

Hepatotoxicity of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs).

Drug-induced liver injury (DILI) is one of the most frequently adverse reactions in clinical drug use, usually caused by drugs or herbal compounds. Compared with other populations, cancer patients are more prone to abnormal liver function due to primary or secondary liver malignant tumor, radiation-induced liver injury and other reasons, making potential adverse reactions from liver damage caused by anticancer drugs of particular concernduring clinical treatment process. In recent years, the application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has changed the treatment status of a series of solid malignant tumors. Unfortunately, the increasing incidence of hepatotoxicitylimits the clinical application of EGFR-TKIs. The mechanisms of liver injury caused by EGFR-TKIs were complex. Despite more than a decade of research, other than direct damage to hepatocytes caused by inhibition of cellular DNA synthesis and resulting in hepatocyte necrosis, the rest of the specific mechanisms remain unclear, and few effective solutions are available. This review focuses on the clinical feature, incidence rates and the recent advances on the discovery of mechanism of hepatotoxicity in EGFR-TKIs, as well as rechallenge and therapeutic strategies underlying hepatotoxicity of EGFR-TKIs.

Decoding the anti-cancer potential of Pexidartinib (PLX3397), a Fms-like tyrosine kinase 3 inhibitor, using next-generation knowledge discovery methods.

Acute Myeloid Leukemia (AML) is a complex hematologic malignancy characterized by the rapid proliferation of abnormal myeloid precursor cells. The FMS-like tyrosine kinase 3 (FLT3), a receptor tyrosine kinase, plays a pivotal role in regulating cell survival, proliferation, and differentiation within the hematopoietic system. Mutations in FLT3, particularly internal tandem duplications (ITDs) and point mutations within the tyrosine kinase domain (TKD), are prevalent in AML and are associated with poor prognosis and increased risk of relapse. The development of targeted therapies has revolutionized the landscape of cancer treatment by focusing on the inhibition of kinase signalling. Small-molecule inhibitors designed to selectively target receptor tyrosine kinases, such as PLX3397, have shown promising results in preclinical studies and early phase clinical trials. PLX3397 exerts its inhibitory effects by targeting CSF1R and KIT, leading to the disruption of receptor tyrosine kinase signalling cascades, suppression of leukemic cell growth, and induction of apoptosis. This study emphasizes the significance of FLT3 as a receptor tyrosine kinase as a therapeutic target for PLX3397. After evaluating the usefulness of PLX3397 as an enzyme inhibitor using ADMET prediction, PLX3397 was prepared for molecular docking in the FLT3 crystal structure (PDB: 4XUF). A molecular dynamics simulation was performed on PLX3397 to evaluate its binding affinity and protein stability in a simulated physiological environment. In conclusion, targeting FLT3 as a receptor tyrosine kinase with PLX3397 represents a promising therapeutic strategy for improving outcomes in patients with FLT3-mutated AML. Further clinical investigations are warranted to validate the efficacy and safety of PLX3397 and to optimize treatment strategies for AML patients based on the FLT3 mutational status.

Affinity purification mass spectrometry characterisation of the interactome of receptor tyrosine kinase proline-rich motifs in cancer.

Receptor tyrosine kinase (RTK) overexpression is linked to the development and progression of multiple cancers. RTKs are classically considered to initiate cytoplasmic signalling pathways via ligand-induced tyrosine phosphorylation, however recent evidence points to a second tier of signalling contingent on interactions mediated by the proline-rich motif (PRM) regions of non-activated RTKs. The presence of PRMs on the C-termini of >40 % of all RTKs and the abundance of PRM-binding proteins encoded by the human genome suggests that there is likely to be a large number of previously unexplored interactions which add to the RTK intracellular interactome. Here, we explore the RTK PRM interactome and its potential significance using affinity purification mass spectrometry and in silico enrichment analyses. Peptides comprising PRM-containing C-terminal tail regions of EGFR, FGFR2 and HER2 were used as bait to affinity purify bound proteins from different cancer cell line lysates. 490 unique interactors were identified, amongst which proteins with metabolic, homeostatic and migratory functions were overrepresented. This suggests that PRMs from RTKs may sustain a diverse interactome in cancer cells. Since RTK overexpression is common in cancer, RTK PRM-derived signalling may be an important, but as yet underexplored, contributor to negative cancer outcomes including resistance to kinase inhibitors.

Small cell lung cancer transformations from non-small cell lung cancer: Biological mechanism and clinical relevance.

Lung cancer is a leading cause of cancer deaths worldwide, consisting of two major histological subtypes: small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). In some cases, NSCLC patients may undergo a histological transformation to SCLC during clinical treatments, which is associated with resistance to targeted therapy, immunotherapy, or chemotherapy. The review provides a comprehensive analysis of SCLC transformation from NSCLC, including biological mechanism, clinical relevance, and potential treatment options after transformation, which may give a better understanding of SCLC transformation and provide support for further research to define better therapy options.