Dr Machaalani on the Interaction Between c-Met and AXL in RCC

Marc Machaalani, MD, research fellow, Department of Medicine, Dana-Farber Cancer Institute, discusses the rationale for examining AXL and its interaction with c-Met, as well as how inhibition of these targets may impact c-Met inhibitors in renal cell carcinoma (RCC).

Notably, Machaalani and colleagues conducted a study that was presented at the 2024 Kidney Cancer Research Summit. c-Met is a receptor tyrosine kinase that is notably overexpressed in kidney cancer, playing a crucial role in the disease’s progression, he begins. Cabozantinib (Cabometyx) is a TKI that, although effective against c-Met, also functions as a nonspecific inhibitor because it simultaneously targets AXL and its ligand, Machaalani explains. This is particularly important since the presence of both AXL and Gas6 have been associated with poor prognosis in patients with kidney cancer, indicating that their inhibition could be beneficial in managing the disease, according to Machaalani. Given this, the study set out to investigate the intricate relationship between AXL and c-Met and to explore whether inhibiting or silencing AXL could influence, prevent, or even overcome the acquired resistance to cabozantinib and other c-Met inhibitors in RCC, he reports.

To delve into this, investigators generated cabozantinib-resistant cells from wild-type cabozantinib-sensitive cells. These resistant cells provided a model to study the mechanisms underlying resistance to cabozantinib and potentially other c-Met inhibitors, he continues. Investigators usedchromatin immunoprecipitation sequencing to perform H3K27 acetylation, a specific post-translational histone modification that is associated with active enhancers and promoters.

In parallel, investigators performed RNA sequencing to investigate the differentially expressed genes between the cabozantinib-sensitive and -resistant cell lines. By analyzing these gene expression profiles, they aimed to uncover the pathways that were either upregulated or downregulated in response to cabozantinib resistance, he adds. To test this hypothesis, investigators used TP-0903, a small molecule inhibitor specifically targeting AXL, to determine whether inhibiting AXL could reverse or mitigate cabozantinib resistance in these resistant cells, Machaalani concludes.