Saturday, April 20, 2024
4/20/2024
PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is a major cause of cancer deaths which is curable if detected early. Unfortunately, many CRC tumors are diagnosed at more advanced stages where cure rates remain low with 20% five-year survival. The EGFR/RAS signaling pathway is a strong driver of CRC when constitutively activated via mutations (KRAS ~40%, BRAF ~10%, NRAS ~5%), but targeted molecular inhibitors, when used alone (EGFRi, BRAFi, MEKi or ERKi), have yielded disappointing survival benefit. To date, it remains difficult to identify the subset of patients who will meaningfully benefit from EGFR/RAS pathway-targeted therapies, likely due to complex resistance mechanisms. A widely held view is that resistance to targeted therapies is due to pre-existence of rare, drug-resistant mutant cells (subclones) that expand and repopulate the tumor following initial successful treatment leading to permanent, clonal resistance. Recently, however, adaptive mutability (AM) of CRC in response to targeted therapies has been reported as a novel, early resistance mechanism. This hypothesis proposes that blocking critical, hard-wired signaling pathways causes a “stress” reaction characterized by the of genotoxic, reactive oxygen species (ROS) and the suppression of DNA mismatch repair enzymes. These early drug-induced changes effectively cause a sub-clonal, hypermutable state that facilitates the eventual emergence of permanently drug-resistant clones. Microsatellite instability (MSI) and other mutator states (i.e. POLE-mutated tumors) are now known to provide a greater probability of checkpoint inhibitor responses. Thus, we hypothesize that the AM induced by EGFR/RAS pathway inhibitors may lead to rapid, sub-clonal, enhanced mutability, and a higher load of neoantigens producing an “MSI-like” state. This hypermutability, if detectable, would portend the higher likelihood of response to checkpoint inhibitors. Traditional analysis of tumor mutation burden (TMB) by NGS assessment of a cancer gene panel would not likely detect genome-wide sub-clonal TMB (scTMB). Standard TMB assays detect bountiful, clonally-expanded mutations fixed in the tumor from the time of its founding. Conversely, we propose that the mutations resulting from a rapid, drug-induced mutator phenotype will likely be present at low variant allele frequencies (i.e. subclonal) that are below the limit of detection of standard NGS approaches. In this proposal, we will test the hypothesis that scTMB occurs in response to targeted therapies, and can be detected using an ultrasensitive and highly specific genome-wide Duplex DNA sequencing assay as an indicator (biomarker) of a mutator state induced by targeted therapies. We propose that the presence of scTMB would predict responses to checkpoint inhibitors, and suggest a benefit to targeted therapies combined with checkpoint inhibitors. These studies will lead to a better molecular understanding of the newly identified “adaptive mutability” resistance mechanism, and potentially provide a solid rationale for the use of combination targeted- and immune-therapies in biomarker-selected patient subpopulations to improve response.
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