Project 2: Role of codon and isoform differences in RAS tumorigenesis Project Leader: Sharon L. Campbell Abstract: RAS genes encode small 21 kD GTPases that cycle between active and inactive states to regulate cellular growth. Approximately one-third of all human cancers contain activating mutations in RAS genes, with codon hotspots at positions 12, 13 and 61. These point mutations render RAS proteins insensitive to down regulation, resulting in chronic RAS activation and constitutive, oncogenic signaling. As such, they have historically been considered oncogenic equivalents. However, recent observations suggest that codon- and residue-specific RAS mutations differ in their ability to function as GTPases switches, engage effectors, and promote signaling and tumorigenesis. Differences have also been observed in the response and resistance to specific anti-cancer therapies. Thus understanding these differences will have important clinical and biological implications. It is also intriguing that cancers display tissue-specific preferences in both RAS mutation and isoform type. To better understand cancer-specific RAS mutation and isoform differences, we propose structural and biochemical characterization studies on the KRAS and NRAS isoforms. These studies will be highly integrated with other components of the P01, and include cell-based and mouse studies to correlate molecular information with RAS activation levels, RAS-mediated signaling and tumorigenesis.
In Aim 1, we will determine whether codon- and residue-specific oncogenic mutations in NRAS and KRAS differentially alter intrinsic RAS function and effector recognition.
In Aim 2, we will determine whether sequence differences in the core GTPase domain of NRAS and KRAS drive isoform-specific differences in intrinsic RAS function, signaling and tumorigenesis.
In Aim 3, we will determine how the activity and tumor promoting properties of KRAS and an oncogenic KRAS mutant (G12C) prevalent in lung cancer are regulated by cysteine oxidation. Characterization of the redox properties of KRAS G12C will aid in anti-cancer efforts to target this oncogenic mutant, as well as understanding distinct the phenotypes of KRAS G12C observed in cell-based and mouse model studies. The proposed studies will help elucidate codon-, residue- and isoform-specific differences that promote RAS-driven cancers, which will inform the development of new and more specific therapies to target aberrant RAS function in cancer.
The three RAS genes comprise the most frequently mutated oncogene family in cancer, making RAS attractive and important anti-cancer drug targets. However, before we can effectively target mutant RAS proteins, we need to better understand how the mutations disrupt structure and function. Our studies will determine mutation-specific protein functions to help design and develop anti-RAS drugs for cancer treatment.
| 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: |
| Vaseva, Angelina V; Blake, Devon R; Gilbert, Thomas S K et al. (2018) KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism. Cancer Cell 34:807-822.e7 |
| 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 |
| Papke, Bjoern; Der, Channing J (2017) Drugging RAS: Know the enemy. Science 355:1158-1163 |
| Bryant, Kirsten L; Der, Channing J (2017) Mutant RAS Calms Stressed-Out Cancer Cells. Dev Cell 40:120-122 |
| 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: |
| 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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