Abstract
RAS (rat sarcoma virus) mutant cancers remain difficult to treat despite the advances in targeted therapy and immunotherapy. Targeted therapies against the components of mitogen-activated protein kinase (MAPK) pathways, including RAS, RAF, MEK, and ERK, have demonstrated activity in BRAF mutant and, in limited cases, RAS mutant cancer. RAS mutant cancers have been found to activate adaptive resistance mechanisms such as autophagy during MAPK inhibition. Here, we review the recent clinically relevant advances in the development of the MAPK pathway and autophagy inhibitors and focus on their application to RAS mutant cancers. We provide analysis of the preclinical rationale for combining the MAPK pathway and autophagy and highlight the most recent clinical trials that have been launched to capitalize on this potentially synthetic lethal approach to cancer therapy.
Highlights
Activating mutations in the RAS oncogene have been studied for decades because of their prevalence in cancer, and because RAS mutant cancers have remained difficult to treat
There are, some active clinical trials that continue to examine single inhibitor Farnesyl transferase inhibitors (FTI) treatments for cancer (NCT04284774; NCT03496766; NCT04865159). These trials are restricted to HRAS mutant cancers, where the sole prenylation method is via farnesyltransferase, preventing the circumvention of FTIs with different compensatory prenylation methods in other cancers [10]
Which node of autophagy should be inhibited in combination with mitogenactivated protein kinase (MAPK) inhibition: lysosomal or non-lysosomal? This remains an open question, but a recent preclinical study has demonstrated that non-lysosomal autophagy inhibition in KRAS mutant pancreatic cells upregulates NRF2-dependent micropinocytosis, an alternative nutrient-scavenging pathway that can rescue cell death
Summary
Activating mutations in the RAS (rat sarcoma virus) oncogene have been studied for decades because of their prevalence in cancer, and because RAS mutant cancers have remained difficult to treat. The challenge with targeting RAS is its high affinity for guanine nucleotides, limiting the development of a GTP-mimetic, and the lack of suitable binding sites for therapeutic ligands [10]. RAS involve inhibiting the downstream pathways that RAS mutant cancers critically rely on to survive and proliferate. ERK is the key effector protein of the MAPK pathway, which drives cell proliferation and survival; RAS-dependent PI3K signaling leads to the phosphorylation of AKT and of downstream mTOR (mechanistic target of rapamycin), which regulates nutrient metabolism and mRNA translation. This review will highlight new developments in the direct and indirect targeting of RAS and focus on combining MAPK and autophagy inhibition as a new strategy in cancer
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