Abstract 3866: Targeting AXL can effectively inhibit c-Met-induced therapeutic resistance in renal cancer
Authors: Sabarwal Akash , Rawat Laxminarayan , Wedel Johannes , Sasamoto Yuzuru , Signoretti Sabina , Choueiri Toni K. , Balan Murugabaskar , Pal Soumitro 
Published: April 2023

Abstract
Advanced stage renal cell carcinoma (RCC) often becomes resistant to the currently available therapeutic options. Receptor Tyrosine Kinase (RTK), c-Met, is overexpressed and hyperactivated in renal cancer; and it promotes tumor-promoting pathways following binding with its ligand, Hepatocyte Growth Factor (HGF). Cabozantinib (Cabo), an inhibitor of c-Met/few other RTKs (like, AXL and KDR), is being used for the treatment of RCC. However, acquired therapeutic resistance is a major hurdle in its clinical use. Mechanism(s) of drug resistance against c-Met inhibition is largely unknown. Although Cabo (XL184) can effectively inhibit c-Met/RTK phosphorylation, very interestingly, we found that, prolonged treatment of Cabozantinib (24 hours, in vitro) increased the expression of total c-Met and AXL in renal cancer cells in a dose-dependent manner. AXL is also overexpressed in RCC and has a novel cross-talk with c-Met. We found that silencing AXL (either by gene knock-down approach or using a specific inhibitor (TP-0903)) markedly down-regulates Cabo-mediated total c-Met expression and enhances apoptosis of human RCC cells. We have also utilized murine model(s) of renal cancer growth (both xenograft and syngeneic), and found that Cabo treatment increases the levels of c-Met and AXL in tumor tissues, and the inhibition of AXL using TP-0903 can markedly inhibit the expression levels of total c-Met and AXL. We observed that HGF-mediated c-Met phosphorylation is short-lived when AXL is silenced. We also found that a lower concentration of Cabo can mediate cancer cell survival; and either the knock-down of AXL or using AXL inhibitor in combination with Cabo can reverse these effects. We have studied the downstream signaling pathways (Akt, ERK1/2 and STAT3) of c-Met, and found that AXL inhibition is crucial to down-regulate c-Met-induced signaling molecules following Cabo treatment. Our observations indicate that Cabo-mediated increase in total c-Met in RCC cells is not regulated at the transcriptional level; however, Cabo can interfere with the receptor degradation pathway leading to increased accumulation of c-Met. We have also studied the levels of c-Met and AXL in renal tumor tissues (archived specimens) from renal cancer patients before and after Cabozantinib treatment. Interestingly, we found increased levels of total c-Met and AXL in tumor tissues following Cabo treatment. Together our data suggest that AXL plays a critical role in mediating therapeutic resistance against c-Met inhibitor; and a combination of Cabo and an AXL/other RTK inhibitor can effectively block the resistance.
Citation Format: Akash Sabarwal, Laxminarayan Rawat, Johannes Wedel, Yuzuru Sasamoto, Sabina Signoretti, Toni K. Choueiri, Murugabaskar Balan, Soumitro Pal. Targeting AXL can effectively inhibit c-Met-induced therapeutic resistance in renal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3866.