Co-targeting kinases and epigenetic regulators for the treatment of Ras-driven lung cancer

Abstract

Lung cancer is the leading cause of cancer deaths worldwide killing over one million people each year. With the advent of targeted therapies, overall survival rates have improved for a subset of lung cancer patients including those with tumors harboring mutations in EGFR, BRAF, and ALK. While KRAS is the most frequently mutated oncogene in lung adenocarcinoma, there are still no effective treatments for these patients. This dissertation characterizes a promising therapeutic combination that targets kinase signaling and epigenetic regulation in KRAS-mutant tumors. Specifically, we show that dual inhibition of MEK and BRD4 triggers cell death and potent tumor regression. Demonstrable tumor regression in this setting is rare, making our work exciting for clinical development. Moreover, we report that this therapeutic efficacy is dependent on the aberrant expression of the homeobox gene, HOXC10. HOXC10 is highly expressed in nearly half of all KRAS mutant tumors and is largely caused by unappreciated defects in PRC2 genes. Importantly, BET bromodomain inhibitors potently suppress HOXC10 expression and this suppression is required for cell death. We further show that HOXC10 and the Ras pathway cooperatively regulate pre-replication complex proteins in these tumors. It is this co-repression that triggers stalled replication, DNA damage, and ultimately cell death. Together this study characterizes a new therapeutic combination and identifies a predictive biomarker of efficacy. We also examine this new subset of lung adenocarcinoma tumors characterized by an aberrant PRC2-HOXC10 axis. Here, we present striking preliminary results that indicate PRC2 defects and high HOXC10 expression may enhance the metastatic capabilities of these tumors. In summary, this dissertation identifies a novel combination treatment, a predictive therapeutic biomarker, and a distinct subset of lung tumors that exhibit high expression of HOXC10. These findings have promising clinical applications and inspire future mechanistic study of the role of HOXC10 in lung tumorigenesis. We hope this work sparks additional studies that target cancer at the intersection of signaling and epigenetics.