RAS genes are the most frequently mutated oncogenes, with prominent prevalence in some of the most aggressive cancers, such as lung or pancreatic tumors. This has led to an intense effort in the development of therapies targeting RAS oncoproteins. However, after more than three decades, no RAS inhibitors have been translated to human clinical investigation. Alternative approaches of blocking up or downstream signaling hubs frequently fail due to the emergence of resistance mechanisms. Hence, therapeutic disruption of RAS addictions remains one of the “Holy Grails” of cancer research and ligand discovery.
The imperative clinical need of RAS-directed therapies is well exemplified by pancreatic cancer. KRAS is mutated in 95% of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, and is a well-validated driver of PDAC growth and maintenance. This tumor type is among the deadliest cancers.
Chromatin-dependent signal transduction and transcription are the point of confluence of the multiple signaling networks elicited by mutant KRAS. Hence, disruption of these gene-regulatory dependencies represents an attractive therapeutic interface less prone to the development of resistance mechanisms. To decipher the gene-regulatory logic imposed by mutant KRAS, I aim to engineer KRAS-degradable pancreatic cancer cell lines. A combination of time-resolved KRAS ablation with unbiased measurements of chromatin remodeling and gene activity will identify the core protein network that sustains KRAS aberrant gene-regulation. To systematically delineate the underlying mechanisms, I will devise KRAS-degradation-dependent transcriptional reporters amenable to phenotypic profiling and will perform genetic and drug screens. I expect to find chemical and genetic means that interfere with KRAS-dependent, transcriptionally active chromatin. Overall, these findings will deliver key vulnerabilities in pancreatic cancer and provide a mechanistic rationale for mimicking KRAS degradation via disruption of transcription regulatory networks. Given the urgent clinical need, there is an enormous potential to initiate preclinical investigation directed to improve the therapeutic opportunities in pancreatic cancer.
