entrectinib and Cell-Transformation--Neoplastic

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.

Topics: Animals; Apoptosis; Bcl-2-Like Protein 11; Benzamides; Cell Line, Tumor; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; ErbB Receptors; Female; HEK293 Cells; Humans; Indazoles; Lung Neoplasms; Male; Mice, Inbred NOD; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Neoplasms; Pancreatic Neoplasms; Protein Kinase Inhibitors; Receptor, trkA