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.