Researchers from the University of California, San Francisco used a genome-scale CRISPR interference (CRISPRi) functional genomics system to methodically identify genetic interactions with a mutant type of KRAS called KRASG12C, and discovered combination treatments that target genes associated with its activity.
Inhibitors targeting KRASG12C are a promising new class of targeted cancer therapeutics, the authors indicated in their study in Science Signaling yesterday. The inhibitors react with the mutant cysteine residue by binding covalently to the switch-II pocket that is existing just in the non-active guanosine diphosphate (GDP)-bound type of KRASG12C, sparing the wild-type protein. In analyzing cellular assays of KRASG12C-mutant lung and pancreatic cancer, the researchers identified the presence of genes that were uniquely crucial in this oncogenic driver-limited cell state.
“We termed such genes ‘collateral dependencies‘ (CDs) and identified two classes of combination therapies targeting these CDs that increased KRASG12C target engagement or blocked residual survival pathways in cells and in vivo.”, the researchers claimed.
In preclinical studies, an advanced-stage KRASG12C inhibitor called ARS-1620 has very particular anticancer activity versus KRASG12C-mutant tumors without any observed dose-limiting toxicity in mice, the researchers noted. Nevertheless, they added, it is probable that KRASG12C-dependent cancer cells will involve formerly dispensable genes and pathways to preserve survival and expansion.
Our study uncovered diverse mechanisms by which collateral pro-oncogenic signaling proteins sustain a mutant KRAS-dependent cancerous phenotype after acute chemical inhibition of KRASG12C
The group hypothesized that such bypass paths with the ability to sustain cancer cell survival are likely to be distinctive from synthetic lethal (SL) reliances, and labeled them collateral dependences (CDs). Utilizing a genome-wide CRISPRi system they determined different mechanisms by which CDs influence KRASG12C-driven growth upon oncogene inactivation.
“This approach identified specialized roles of known RAS signaling components and highlights CDs involved in transcriptional regulation and other cellular processes outside the core RAS pathway,” the researchers claimed.
The researchers after that utilized pharmacology to evaluate therapeutically targetable CDs and discovered that chemical inhibition of both recognized and unforeseen RAS pathway genes led to KRASG12C inhibition. In exploring the mechanisms of these compound interactions, they further found that these combination therapies either directly accepted switch-II pocket inhibition to enhance KRASG12C target interaction or separately blocked residual survival pathways.
“Our study uncovered diverse mechanisms by which collateral pro-oncogenic signaling proteins sustain a mutant KRAS-dependent cancerous phenotype after acute chemical inhibition of KRASG12C.”, the researchers claimed.
Notably, the researchers additionally kept in mind that their research study revealed that single-target inhibition of the most well-validated oncogenic drivers can be restricted by CDs that help sustain oncogenic phenotypes in the driver-limited state.
“The concept that a cancerous phenotype can be driven by the activity of a single oncogene is being revised given that, beyond BCR-ABL inhibitors in chronic myelogenous leukemia, targeted therapies have fallen short on their promise of promoting durable responses and cures for patients,” the researchers concluded.
Kevin Lou, Veronica Steri, Alex Y. Ge, Y. Christina Hwang, Christopher H. Yogodzinski, Arielle R. Shkedi, Alex L. M. Choi, Dominique C. Mitchell, Danielle L. Swaney, Byron Hann, John D. Gordan, Kevan M. Shokat and Luke A. Gilbert. KRASG12C inhibition produces a driver-limited state revealing collateral dependencies. Science Signaling. Published online May 28, 2019. doi: 10.1126/scisignal.aaw9450