Targeting sequential vulnerabilities in treatment-resistant BRAF mutated lung cancers
A multi-approach study conducted by researchers from the Laboratory of Biology of Tumor and Development (GIGA-Cancer, ULiège), together with their local and international partners, highlights new therapeutic vulnerabilities in drug tolerant and resistant BRAF mutated lung adenocarcinoma. This discovery paves the way to better patient care and allow to consider/test new treatment options for this highly aggressive neoplasm.
In lung adenocarcinoma, BRAF mutations are found in about 5% of cases, with both V600E and non-V600E mutations equally represented. However, only patients with the V600E mutation receive targeted therapies. The standard treatment involves a dual inhibition of BRAF and MEK kinases, typically using a combination of dabrafenib and trametinib. This approach has been shown to improve response rates and extend progression-free survival compared to single-agent treatments. Unfortunately, similar to most targeted therapies blocking a “driver oncogene”, the initial clinical response to targeted kinase inhibitors is almost always temporary, with tumors invariably resisting/progressing.
To date, acquisition of resistance to targeted therapies is one of the greatest challenges faced by precision oncology, with immediate consequences for patient care. Drug tolerant cancer cells are considered as the reservoir from which genetically resistant cells subsequently emerge. By using whole-genome CRISPR screening and RNA sequencing, this study characterized the vulnerabilities of both persister and resistant cellular models. Dabrafenib and trametinib treatment amplifies oxidative stress and concurrently induces antioxidant responses. “However, the characteristics of oxidative damage, the selection of redox detoxification systems, and the resulting therapeutic vulnerabilities vary depending on the stage of the disease”, explains Marie-Julie Nokin. Indeed, persister cells experience lipid peroxidation and are vulnerable to ferroptosis induction. In contrast, in resistant cells, reactivation of the MAPK signaling pathway increases defense mechanisms against ferroptosis. Similar to BRAFV600E-mutant melanoma, histone deacetylase inhibitors reduce the viability of these resistant cells. Altogether, these crucial findings open the way to potential new treatments to fight disease relapse in the clinic.
This study, conducted by Marie-Julie Nokin (Assistant professor, ULiège), was initiated in the Laboratory of Dr. David Santamaria at the University of Bordeaux (France). The work was partly funded by the FNRS-Télévie and the Foundation Leon Fredericq. It benefited from the support of GIGA’s technological platforms, especially the in vitro imaging and the viral vectors facilities. This collaborative research also involved numerous ULiège researchers and international collaborators.
