Wednesday, April 2, 2025
4/2/2025
Directed Clonal Evolution of Drug Resistant BRAF Mutant Melanoma for Cross-Sensitization to MAPK Hyperactivation - PROJECT SUMMARY/ABSTRACT Targeted cancer therapeutics have traditionally focused on inhibiting activated oncogenic signaling pathways. While such pathway inhibitors have resulted in clinical successes with improved patient response rates and progression free survival, in most cases, they have yet to yield curative responses due to eventual drug resistance. Emerging evidence suggests that context-dependent lethality induced by pathway activation represents a promising unexplored approach for cancer therapeutics with the potential to overcome resistance. The main goal of this project is to demonstrate cancers developing resistance to targeted therapy will gain increased sensitivity to non-cross-resistant, pathway-hyperactivation. Specifically, this project will focus on melanoma, where oncogenic ERK MAPK pathway activation motivated the development of MAPK pathway inhibitors. BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are used in combination as the standard of care for targeted therapy in BRAFV600E melanoma patients. However, current treatment options, including these targeted therapies and immunotherapies, rarely achieve complete responses due to intrinsic and acquired resistance. Although resistance to MAPK pathway inhibition is predominantly mediated by MAPK reactivation, the intratumoral heterogeneity of resistance mechanisms complicate and curtail efforts to combat resistance. Increased susceptibility to MAPK hyperactivation occurs through the same mechanisms that make cells resistant to BRAFi/MEKi, suggesting cycling treatment for MAPK inhibition followed by MAPK activation would induce collateral sensitivity and avoid resistance development. This proposal will employ high complexity cellular barcode tracing as well as BRAFi/MEKi resistant xenograft models to investigate the efficacy of driving tumor clonal evolution toward BRAFi/MEKi resistance for maximal sensitivity to lethal MAPK hyperactivation resulting in tumor eradication. Furthermore, dual-knockout CRISPR screening strategies will be employed to identify the molecular mechanisms mediating MAPK hyperactivation lethality. The proposed therapeutic approach is based on 1) preliminary work observing selective sensitivity of MAPKi resistant melanoma to lethal MAPK hyperactivation and 2) non-cross resistance mechanisms for MAPK inhibition and hyperactivation. By exploring the synergy between established targeted therapy strategies and previously unappreciated pathway activation cancer dependencies, these studies aim to establish a new therapeutic paradigm for cancer treatment. This approach is likely broadly applicable to other key oncogenic signaling pathways and cancer types and addresses one of the fundamental limitations of targeted therapies.
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