Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer |
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| Authors: | Jatin Roper Mark J Sinnamon Erin M Coffee Peter Belmont Lily Keung Larissa Georgeon-Richard Wei Vivian Wang Anthony C Faber Jihye Yun Ömer H Yilmaz Roderick T Bronson Eric S Martin Philip N Tsichlis Kenneth E Hung |
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| Institution: | 1. Tufts Medical Center, Division of Gastroenterology, Department of Medicine, Boston, MA, United States;2. Massachusetts General Hospital, Center for Systems Biology, Boston, MA, United States;3. Massachusetts General Hospital Cancer Center, Boston, MA, United States;4. Celgene, Discovery, Oncology Research, San Diego, CA, United States;5. Tufts Medical Center, Molecular Oncology Research Institute, Boston, MA, United States;6. Weill Cornell Medical College and New York-Presbyterian Hospital, Department of Medicine, New York, NY, United States;g The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States;h Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA, United States;i Pfizer Biotherapeutics Clinical Research, Cambridge, MA, United States |
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| Abstract: | PI3K inhibition in combination with other agents has not been studied in the context of PIK3CA wild-type, KRAS mutant cancer. In a screen of phospho-kinases, PI3K inhibition of KRAS mutant colorectal cancer cells activated the MAPK pathway. Combination PI3K/MEK inhibition with NVP-BKM120 and PD-0325901 induced tumor regression in a mouse model of PIK3CA wild-type, KRAS mutant colorectal cancer, which was mediated by inhibition of mTORC1, inhibition of MCL-1, and activation of BIM. These findings implicate mitochondrial-dependent apoptotic mechanisms as determinants for the efficacy of PI3K/MEK inhibition in the treatment of PIK3CA wild-type, KRAS mutant cancer. |
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| Keywords: | PI3K MEK KRAS Colorectal cancer Mouse model of cancer |
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