Inhibition of MEK1/2 Forestalls the Onset of Acquired Resistance to Entrectinib in Multiple Models of NTRK1-Driven Cancer
Aria Vaishnavi,
Michael T. Scherzer,
Conan G. Kinsey,
Gennie L. Parkman,
Amanda Truong,
Phaedra Ghazi,
Sophia Schuman,
Benjamin Battistone,
Ignacio Garrido-Laguna,
Martin McMahon
Affiliations
Aria Vaishnavi
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
Michael T. Scherzer
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA
Conan G. Kinsey
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Internal Medicine, Division of Oncology, University of Utah, Salt Lake City, UT 84112, USA
Gennie L. Parkman
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA
Amanda Truong
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA
Phaedra Ghazi
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA
Sophia Schuman
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
Benjamin Battistone
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
Ignacio Garrido-Laguna
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Internal Medicine, Division of Oncology, University of Utah, Salt Lake City, UT 84112, USA
Martin McMahon
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA; Department of Dermatology, University of Utah, Salt Lake City, UT 84112, USA; Corresponding author
Summary: 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.
