Dr Machaalani on Overcoming Acquired Resistance Through AXL and c-Met Inhibition in RCC

Marc Machaalani, MD, research fellow, Department of Medicine, Dana-Farber Cancer Institute, discusses the pro-tumorigenic role of AXL through its interaction with c-Met and how inhibition of these targets may prevent acquired resistance to c-Met inhibitors in renal cell carcinoma (RCC).

Machaalani and colleagues conducted a study to evaluate the crosstalk between AXL and c-Met and explore the potential of targeting AXL to prevent resistance to c-Met inhibition. In this study, a cabozantinib (Cabometyx)-resistant cell line was generated from wild-type cabozantinib-sensitive Caki-1 clear cell RCC (ccRCC) cells, and CRISPR/Cas9-mediated AXL knockout cells were produced from 786-O ccRCC cells.

Results presented at the 2024 Kidney Cancer Research Summitrevealed that cells resistant to cabozantinib and c-MET inhibitors exhibit distinct transcriptomic and epigenomic profiles, Machaalani reports. Findings showed differentially marked H3K27ac regions and up- or downregulated genes and pathways in cabozantinib-resistant cells compared with cabozantinib-sensitive cells. RNA sequencing also showed that epithelial-mesenchymal transition, hypoxia, and KRAS signaling pathways were significantly downregulated in AXL knockout cells compared with control 786-O cells. These findings indicate that cells repeatedly exposed to c-Met inhibition undergo epigenetic rewiring, leading to downstream transcriptomic and phenotypical changes, such as resistance, Machaalani states.

Collaborating with Boston Children’s Hospital, the research team found that AXL and c-Met are overexpressed and form a complex in kidney cancer cells compared with primary renal proximal tubule epithelial cells, he continues. Upon c-Met inhibition, novel expression of AXL and c-Met was observed, along with increased c-Met and AXL expression in RCC and c-Met phosphorylation in the presence of HGF, Machaalani details.

Moreover, silencing AXL with an AXL-specific small molecule inhibitor, TP-0903, was found to block cabozantinib-mediated increases in c-Met expression and induce apoptosis in cabozantinib-resistant cells, Machaalani says. These findings indicate that targeting AXL alongside c-Met could overcome or even prevent the development of resistance to cabozantinib in patients with RCC, Machaalani concludes.