Abstract 4555: c-Met/AXL crosstalk in mediating therapeutic resistance in renal cell carcinoma

Le résumé fourni par la source

Abstract Receptor Tyrosine Kinase (RTK), c-Met, is overexpressed in renal cancer and correlates with a decreased survival rate. Upon binding with its specific ligand, Hepatocyte Growth Factor (HGF), c-Met activates pro-tumorigenic signaling. c-Met/RTK inhibitors are used for the treatment of advanced renal cell carcinoma (RCC). However, acquired therapeutic resistance is a major clinical problem and the underlying mechanisms are largely unknown. Hence, novel therapeutic targets are needed to overcome the clinical hurdles; and the RTK, AXL, can be a potential target. AXL is overexpressed and a poor prognostic marker in RCC. AXL overexpression drives wide-ranging processes, including epithelial-to-mesenchymal transition (EMT), tumor angiogenesis, and resistance to chemotherapeutics. Cabozantinib (XL184/Cabo), is approved for advanced-stage RCC and can inhibit c-Met and VEGFR2 activation (including AXL and a few other RTKs); however, it is not a specific/potent inhibitor of AXL. Hence, inhibiting c-Met alone may not be sufficient when AXL remains active. Therefore, the pro-tumorigenic role of AXL and its cross-talk with c-Met in renal cancer need to be thoroughly investigated. We compared the expression of c-Met and AXL in TCGA and found significantly high expression of both c-Met and AXL in primary renal tumor tissues compared to normal tissues. Our data showed that AXL forms a complex with c-Met and may have a significant cross-talk which can be involved in therapeutic resistance. We have also found that prolonged treatment of c-Met inhibitor Cabo, (including Crizotinib and PF-4217903) induced c-Met and AXL overexpression in RCC cells. Interestingly, c-Met inhibitor(s)-induced overexpressed c-Met can also be increasingly phosphorylated (at low concentrations) in the presence of HGF, which may cause enhanced downstream tumor-promoting signaling. To understand the role of AXL in tumor-promoting pathways and therapeutic resistance, we have generated CRISPR/Cas9-mediated AXL knock-out cells (AXL-KO) and found that silencing AXL can prevent c-Met-inhibitor(s)-mediated c-Met overexpression. Furthermore, to identify the effect of AXL-KO on pro-tumorigenic signaling, transcriptional profiles of control clones and AXL-KO cells were compared. The gene set enrichment analysis (GSEA) showed that genes involved in ‘EMT’, ‘Hypoxia’, and ‘K-Ras’ signaling pathways were significantly downregulated. We have also utilized an AXL-specific small molecule inhibitor, TP-0903, in combination with Cabo and validated our data. We have also generated a Cabo-resistant cell line (Caki-1) and found high expression of c-Met and AXL in these cells. Furthermore, either silencing of AXL (using siRNA) or inhibiting AXL (using TP0903) induced significant apoptosis in these Cabo-resistant cells. Together, our data suggest that inhibition of AXL along with c-Met can be beneficial in preventing acquired therapeutic resistance in RCC. Citation Format: Akash Sabarwal, Laxminarayan Rawat, Johannes Wedel, Murugabaskar Balan, Gwo-Shu Mary Lee, Toni K. Choueiri, Soumitro Pal. c-Met/AXL crosstalk in mediating therapeutic resistance in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4555.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.