This proposal seeks effective combination therapies that maximize GIST response to KIT/PDGFRA inhibition by concurrently targeting the biologically key MEK/MAPK pathway. Most GISTs express mutant, constitutively activated forms of the KIT or PDGFRA, and we have shown that these formerly untreatable cancers can be palliated in 80% of patients by oral single-agent therapy with imatinib mesylate. However,patients responding to imatinib have persistent measurable disease and generally develop resistance within two years of starting treatment. Therefore, more effective and broader-spectrum therapies are urgently needed. Notably, our preliminary studies show that KIT/PDGFRA imatinib resistance mechanisms vary from patient to patient, and also between metastatic lesions in a given patient, but uniformly rely upon MEK/MAPK signaling to support cell proliferation.
In Aim 1, by studying MEK/MAPK signaling and response mechanisms, we will develop clinically-relevant biomarkers and - most importantly - we will identify alternate MEK-dependent therapeutic targets which might have greater specificity, in GIST, compared to MEK.
In Aim 2. we will characterize mechanisms of MEKi resistance, since such studies are likely to identify biologically essential regulatory nodes in MEK/MAPK-pathways, which - like those found in Aim 1 - will be candidates as biomakers and therapeutic targets in GIST clinical trials. The collective studies in Aims 1-2, by revealing the scope of MEK/MAPK signaling in GIST, will provide the understanding needed to design more effective and less toxic clinical trials.
In Aim 3 we evaluate combination therapies with imatinib and MEKi, as a strategy to inhibit downstream signals from the varied gain-of-function KIT mutations each imatinib-resistant patient, while maintaining imatinib inhibition of nonprogressing GIST subclones. This will be accomplished through a phase l/ll clinical trial of the MEK inhibitor, MEK162, combined with imatinib, in patients showing progression of metastatic GIST on imatinib or sunitinib. Through these studies, we will translate the basic science proposed in this SPORE through to clinical application.

Public Health Relevance

We expect this GIST research will enable clinical progress by developing therapies that are not stymied by the diversity of KIT/PDGFRA inhibitor resistance mechanisms. The proposed studies seek to maximize response by targeting KIT/PDGFRA oncogenic signals as they pass through the MEK/MAPK conduit, and such strategies are also relevant in other kinase-driven human cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (J1))
Program Officer
Agarwal, Rajeev K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
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
Danai, Laura V; Babic, Ana; Rosenthal, Michael H et al. (2018) Altered exocrine function can drive adipose wasting in early pancreatic cancer. Nature 558:600-604
Grasso, Catherine S; Giannakis, Marios; Wells, Daniel K et al. (2018) Genetic Mechanisms of Immune Evasion in Colorectal Cancer. Cancer Discov 8:730-749
Corcoran, Ryan B; André, Thierry; Atreya, Chloe E et al. (2018) Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer. Cancer Discov 8:428-443
Song, Mingyang; Wu, Kana; Meyerhardt, Jeffrey A et al. (2018) Fiber Intake and Survival After Colorectal Cancer Diagnosis. JAMA Oncol 4:71-79
Babic, A; Schnure, N; Neupane, N P et al. (2018) Plasma inflammatory cytokines and survival of pancreatic cancer patients. Clin Transl Gastroenterol 9:145
Lopes-Ramos, Camila M; Kuijjer, Marieke L; Ogino, Shuji et al. (2018) Gene Regulatory Network Analysis Identifies Sex-Linked Differences in Colon Cancer Drug Metabolism. Cancer Res 78:5538-5547
Van Blarigan, Erin L; Ou, Fang-Shu; Niedzwiecki, Donna et al. (2018) Dietary Fat Intake after Colon Cancer Diagnosis in Relation to Cancer Recurrence and Survival: CALGB 89803 (Alliance). Cancer Epidemiol Biomarkers Prev 27:1227-1230
Patra, Krushna C; Kato, Yasutaka; Mizukami, Yusuke et al. (2018) Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism. Nat Cell Biol 20:811-822

Showing the most recent 10 out of 590 publications