The RAS oncogenes (HRAS, KRAS and NRAS) comprise the most frequently mutated oncogene family in cancer. Despite more than three decades of intensive effort, presently no effective RAS-targeted therapies have reached the clinic. Contributing to this failure have been missteps and mistakes made in drug development, resulting from the field underestimating the complexities of RAS. While recent cancer genome sequencing studies have provided a more comprehensive genetic portrait of specific cancers, they have also verified that RAS mutations are the major drivers of cancers that comprise three of the four major causes of cancer deaths in the US (lung, colorectal and pancreatic cancer). A RAS Renaissance has now begun, with renewed intense interest and effort to identify and develop new pharmacologic strategies to target aberrant RAS function for cancer treatment. Our rationale for this Program Project is based on our belief that key issues regarding RAS function remain to be resolved and that their resolution will be vital to facilitate more knowledgeable and effective approaches for anti-RAS drug discovery. Our overall premise is that RAS mutations are not created equal. Our overarching hypotheses are that there are significant differences among RAS isoforms and RAS mutations, and that these have distinct oncogenic consequences in different cancers. Four Projects comprise our P01, each led by a long-standing RAS researcher who brings complementary and distinct experimental expertise to a Program designed for strong inter-project collaborations that leverage our strengths and minimize our weaknesses. Collectively, we will produce a cohesive and comprehensive study that could not be achieved by individual laboratories working on their own. Our structural, biochemical and biological efforts will identify RAS isoform- and mutation-specific perturbations to RAS function. In the long term, these distinct perturbations may represent targetable vulnerabilities that will reveal new approaches to develop mutation-specific anti-RAS therapies for cancer treatment. Project 1 focuses on cellular studies of KRAS mutations in pancreatic cancer, closely coordinated with the structural and biochemical studies of KRAS in Project 2. Project 2 studies of NRAS are complemented by Project 3 studies of mutant NRAS and wild type RAS alleles in melanoma. Project 4 will use genetically engineered mouse models of lung cancer to address the basis for the preferential mutation of KRAS in cancer. Core A will provide financial oversight, administrative coordination of information exchange, and biostatistics support across this inter-institutional Program Project. Core B will provide innovative proteomics technologies for unbiased profiling of RAS mutation-selective effector signaling. Our Program findings will help to reshape anti-RAS drug discovery with the goal of developing therapies targeting specific subsets of RAS mutations. Relevance to Public Health: RAS mutations are very common in three of the top four causes of US cancer deaths. Development of effective anti-RAS treatment strategies will significantly reduce the loss of productivity and human lives to cancer.

Public Health Relevance

The three RAS genes comprise the most frequently mutated gene family in cancer, with highest frequencies seen in three of the top four causes of cancer deaths in the US. This Program Project aims to better understand the complexities of RAS oncoproteins to guide efforts to develop anti-RAS drugs for cancer treatment. Anti-RAS drugs are expected to make a significant impact on cancer deaths in the US.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Watson, Joanna M
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Fu, Jingjing; Dang, Yunkun; Counter, Christopher et al. (2018) Codon usage regulates human KRAS expression at both transcriptional and translational levels. J Biol Chem 293:17929-17940
Adhikari, Hema; Counter, Christopher M (2018) Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability. Nat Commun 9:3646
Waters, Andrew M; Der, Channing J (2018) KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med 8:
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Waters, Andrew M; Ozkan-Dagliyan, Irem; Vaseva, Angelina V et al. (2017) Evaluation of the selectivity and sensitivity of isoform- and mutation-specific RAS antibodies. Sci Signal 10:
Ali, Moiez; Kaltenbrun, Erin; Anderson, Grace R et al. (2017) Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance. Nat Commun 8:15617
Yin, Guowei; Kistler, Samantha; George, Samuel D et al. (2017) A KRAS GTPase K104Q Mutant Retains Downstream Signaling by Offsetting Defects in Regulation. J Biol Chem 292:4446-4456
Huynh, Minh V; Campbell, Sharon L (2016) Getting a Handle on RAS-targeted Therapies: Cysteine Directed Inhibitors. Mini Rev Med Chem 16:383-90

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