Mutations in the KRAS oncogene occur in 40% of colorectal cancers (CRC), and despite extensive investigation, KRAS mutated CRCs remain resistant to available targeted therapy strategies. Mutant KRAS has been linked to activation of multiple signaling pathways that promote cancer growth and survival including the MEK-ERK, PI3K and NF-?B pathways. Suppressing critical downstream signaling pathways, either alone or in combination, have evolved as promising treatment strategies. This proposal consists of innovative translational laboratory and clinical studies that focus on developing novel strategies to treat KRAS mutant CRCs. These investigations have already begun to yield strategies that will be assessed in clinical trials in this proposal. Our overarching aim is to substantively advance the treatment of KRAS mutant CRCs in this funding period. We have conducted comprehensive signaling studies, genetic screens, and drug screens to identify and validate genes downstream from KRAS whose expression is essential to the growth and survival of KRAS mutant cancers. Our analyses of 1000 cell lines treated with >200 drugs revealed that MEK inhibitors are the most effective class of agents against KRAS mutant CRC cell lines. However, single agent MEK inhibition appears minimally effective in clinical trial;as such we will develop novel combination strategies that utilize MEK inhibitors as a backbone for KRAS mutant CRC. We recently discovered that combining an IGF-IR inhibitor, which has minimal activity as a single-agent, with a MEK inhibitor is highly effective in KRAS mutant CRC cell lines in vitro and in vivo, leading to the development of a soon to open phase l/II clinical trial of this combination. To discover additional combinations, we developed an innovative pooled shRNA screen to identify MEK inhibitor-based combinations for KRAS mutant CRCs. One gene identified in the screen was BCL-XL, and initial studies demonstrate that inactivation of BCL-XL potently synergizes with MEK inhibitors both in vitro and in vivo, which we will further explore in the laboratory and in planned clinical trials. Finally, we will build on our preliminary data demonstrating that Tank Binding Kinase (TBK1) activity is required for KRAS mutant cell survival. We will examine combined TBK1 inhibitors alone and combined with MEK inhibitors. The studies in this proposal will span cell lines, genetically engineered mouse models and clinical trials to identify novel therapeutic strategies for the treatment of KRS mutant CRCs.

Public Health Relevance

While treatment options have expanded for patients in the past decade and median survival is 2 years, metastatic colorectal cancer (CRC) is largely not curable and there are wide range of outcomes experienced by patients with metastatic CRC. It is clear that differences in outcomes are partly due to different molecular make-ups of tumors. Up to 40% of patients with metastatic CRC have a mutation of a particular gene, KRAS. The goal of this project is to understand more about this group of CRC and find new therapies for these patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
Ma, Siyuan; Ogino, Shuji; Parsana, Princy et al. (2018) Continuity of transcriptomes among colorectal cancer subtypes based on meta-analysis. Genome Biol 19:142
Guercio, Brendan J; Zhang, Sui; Niedzwiecki, Donna et al. (2018) Associations of artificially sweetened beverage intake with disease recurrence and mortality in stage III colon cancer: Results from CALGB 89803 (Alliance). PLoS One 13:e0199244
Neumeyer, Sonja; Banbury, Barbara L; Arndt, Volker et al. (2018) Mendelian randomisation study of age at menarche and age at menopause and the risk of colorectal cancer. Br J Cancer 118:1639-1647
Aguirre, Andrew J; Nowak, Jonathan A; Camarda, Nicholas D et al. (2018) Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine. Cancer Discov 8:1096-1111
Hill, Margaret A; Alexander, William B; Guo, Bing et al. (2018) Kras and Tp53 Mutations Cause Cholangiocyte- and Hepatocyte-Derived Cholangiocarcinoma. Cancer Res 78:4445-4451
He, Xiaosheng; Wu, Kana; Ogino, Shuji et al. (2018) Association Between Risk Factors for Colorectal Cancer and Risk of Serrated Polyps and Conventional Adenomas. Gastroenterology 155:355-373.e18
Van Blarigan, Erin L; Fuchs, Charles S; Niedzwiecki, Donna et al. (2018) Marine ?-3 Polyunsaturated Fatty Acid and Fish Intake after Colon Cancer Diagnosis and Survival: CALGB 89803 (Alliance). Cancer Epidemiol Biomarkers Prev 27:438-445
Hu, Yang; Ding, Ming; Yuan, Chen et al. (2018) Association Between Coffee Intake After Diagnosis of Colorectal Cancer and Reduced Mortality. Gastroenterology 154:916-926.e9
Cao, Yin; Wu, Kana; Mehta, Raaj et al. (2018) Long-term use of antibiotics and risk of colorectal adenoma. Gut 67:672-678
Barry, Joseph D; Fagny, Maud; Paulson, Joseph N et al. (2018) Histopathological Image QTL Discovery of Immune Infiltration Variants. iScience 5:80-89

Showing the most recent 10 out of 590 publications