More than 140,000 Americans are diagnosed with colorectal cancer (CRC) each year and almost 52,000 individuals die from it. Decreasing the frequency of CRC-related death will undoubtedly require tailoring an individual's treatment to the specific mutations that have occurred in their cancer. Activating mutations in the K-Ras oncoprotein are common in CRC and are associated with particularly poor response to both conventional and targeted therapies. For example, the strong association between mutant K-Ras and resistance to anti-EGFR therapy led the American Society for Clinical Oncology to recommend that all cancer patients undergo K-Ras mutation testing prior to receiving treatment. Nevertheless, new clinical and experimental data have called into question the universality of therapeutic resistance associated with mutant K-Ras. Patients with specific K-Ras activating mutations, such as G13D, appear to benefit from anti-EGFR therapy, just like K-Ras wild-type patients. Building upon our expertise in studying Ras-mutant CRC in mouse models (Haigis et al. Nat. Genet. 40: 600-608, 2008; Wang et al. Cancer Disc. 3: 294-307, 2013), we will perform an in-depth analysis of the relationship between specific K-Ras mutations and therapeutic response. This work is separated into four related specific aims: (1) To comprehensively characterize the K-Ras mutational spectrum and to identify co-occurring mutations in primary human CRCs, (2) To generate an allelic series of Cre-dependent K-Ras activating alleles in mice, (3) To measure the molecular, cellular, and tissue-level phenotypes associated with different K-Ras mutations in a mouse model of CRC, and (4) To evaluate the efficacy of EGFR and MEK inhibitors in mouse models of CRC expressing different mutant alleles of K-Ras. In the end, the K-Ras mutant mouse models developed in this project will reveal genetic subpopulations of CRC patients that will benefit from specific targeted therapies.

Public Health Relevance

Our overarching goal is to develop a panel of mouse models of colorectal cancer that can be used as a platform for preclinical evaluation of therapeutic strategies. Here, we will generate an allelic series of genetically engineered mice with distinct K Ras activating mutations and cross them to animals carrying a mutation in Apc to generate a series of K-Ras mutant colorectal cancer models. These studies will be critical for identifying genetic subgroups of colorectal cancer patients that will benefit from therapies targeting EGFR and MEK.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA195744-03
Application #
9390745
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Watson, Joanna M
Project Start
2015-12-15
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Haigis, Kevin M (2017) KRAS Alleles: The Devil Is in the Detail. Trends Cancer 3:686-697
Poulin, Emily J; Haigis, Kevin M (2017) No back seat for a progression event-K-RAS as a therapeutic target in CRC. Genes Dev 31:333-335