2. Academic Validation
  3. Inhibition of MEK1/2 Forestalls the Onset of Acquired Resistance to Entrectinib in Multiple Models of NTRK1-Driven Cancer

Inhibition of MEK1/2 Forestalls the Onset of Acquired Resistance to Entrectinib in Multiple Models of NTRK1-Driven Cancer

  • Cell Rep. 2020 Aug 4;32(5):107994. doi: 10.1016/j.celrep.2020.107994.
Aria Vaishnavi 1,  Michael T Scherzer 2,  Conan G Kinsey 3,  Gennie L Parkman 2,  Amanda Truong 2,  Phaedra Ghazi 2,  Sophia Schuman 1,  Benjamin Battistone 1,  Ignacio Garrido-Laguna 3,  Martin McMahon 4
Affiliations

Affiliations

  • 1 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
  • 2 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.
  • 3 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.
  • 4 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. Electronic address: [email protected].
PMID: 32755586 DOI: 10.1016/j.celrep.2020.107994
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.

Keywords

NTRK gene fusion; colorectal cancer; kinase oncoproteins; lung cancer; pancreatic cancer; pathway-targeted therapies.

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