Epigenetic based therapeutic strategies to drive differentiation and death in KRAS mutant colorectal cancers

Abstract

Colorectal cancer (CRC) is one of the leading causes cancer deaths worldwide, and advanced metastatic disease is still incurable. Mutations in the KRAS oncogene occur in 30-50% of all CRC and render the malignancy resistant to standard of care targeted treatments, such as EGFR inhibitors. Thus, there is significant unmet clinical need for treatments for CRC, especially those with activating mutations in KRAS. Many drugs that target classic oncogenic kinases, such as MEK inhibitors, are ineffective therapies as single agents. One approach is to develop effective combination therapies to co-target orthogonal epigenetic regulators that govern differentiation state and cell plasticity that might enhance the sensitivity of cells to MEK inhibitors. This dissertation describes a promising therapeutic combination to co-target oncogenic RAS signaling and EZH2, the catalytic component of the epigenetic regulator, the Polycomb Repressive Complex 2 (PRC2). PRC2 is a highly conserved developmental regulator that maintains cellular identity by dynamically silencing key genes involved in differentiation. Alterations in PRC2 have been shown to play a driving role in many cancers. EZH2 is found to be commonly overexpressed in solid tumors, but nevertheless, the role of EZH2 in solid tumors, such as CRC has not been sufficiently explored. Specifically, EZH2 is overexpressed in 66% of CRC, and its expression appears to inversely correlate with patient survival and advanced disease. Interestingly, we have found that EZH2 inhibitors are frequently effective when combined with MEK inhibitors in KRAS mutant CRC to clamp down on crucial oncogenic signals at both the kinase level and the transcriptional level. Using a combinatorial and unbiased transcriptomic and epigenomic analysis, we find that EZH2/MEK inhibitors kill KRAS mutant CRC by inducing a shift in the differentiation state of the cell and broadly suppressing oncogenic intestinal Wnt signaling pathways. Once differentiated, EZH2/MEK inhibitors kill CRCs by cooperatively triggering apoptotic signals by upregulating the pro-apoptotic protein BMF. Together, these findings identify a promising therapeutic strategy for advanced CRC and illustrate a new paradigm for epigenetic-based combination therapies to treat aggressive tumor types.