Periodic Reporting for period 1 - ChemRAS (Chemical probing of transcriptional RAS effectors)
Período documentado: 2019-02-15 hasta 2021-02-14
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.
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.
The key milestone of the project has been achieved. Therefore, cellular models that allow acute degradation of mutant KRAS at will have been engineered. Due to the urgent clinical need, pancreatic cancer is the disease background in which the cellular modes were engineered. In addition, the fast biology underlying acute KRAS targeted degradation has been characterized at the level of chromatin remodeling and transcriptional dysregulation. Chromatin reporters will allow the identification of genetic and chemical perturbations that mimic the effect of KRAS degradation at the level of chromatin regulation, with a foreseen enormous therapeutic potential.
In terms of exploitable results, and beyond the scope of the proposed project, the availability of the constructs and cell models generated during the project will be of high value as tools to, overall, understand mutant KRAS signaling. The engineered models will also enable the investigation of resistance mechanisms, arguably the most important problem faced in cancer treatment and that also applies to RAS-related therapies. Overall, there is a remarkable potential impact on society given that the results of this project are expected to shed light on pancreatic cancer treatment options, which remains to be one of the most lethal human malignancies. In addition, research aiming to unravel the molecular biology and therapeutic innovation centered around pancreatic cancer is timely and in line with the current European research trends and societal needs.