Abstract
NTRK1 gene fusions are actionable drivers of numerous human malignancies. Here, we show that expression of the TPR-NTRK1 fusion kinase in immortalized mouse pancreatic ductal epithelial (IMPE) (pancreas) or mouse lung epithelial (MLE-12) cells is sufficient to promote rapidly growing tumors in mice. Both tumor models are exquisitely sensitive to targeted inhibition with entrectinib, a tropomyosin-related kinase A (TRKA) inhibitor. Initial regression of NTRK1-driven tumors is driven by induced expression of BIM, such that BIM silencing leads to a diminished response to entrectinib in vivo. However, the emergence of drug-resistant disease limits the long-term durability of responses. Based on the reactivation of RAF>MEK>ERK signaling observed in entrectinib-treated tumors, we show that the combination of entrectinib plus the MEK1/2 inhibitor cobimetinib dramatically forestalls the onset of drug resistance in vivo. Collectively, these data provide a mechanistic rationale for rapid clinical deployment of combined inhibition of TRKA plus MEK1/2 in NTRK1-driven cancers.
Original language | English (US) |
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Article number | 107994 |
Journal | Cell Reports |
Volume | 32 |
Issue number | 5 |
DOIs | |
State | Published - Aug 4 2020 |
Externally published | Yes |
Keywords
- colorectal cancer
- kinase oncoproteins
- lung cancer
- NTRK gene fusion
- pancreatic cancer
- pathway-targeted therapies
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology