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.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Bcl-2-Like Protein 11 / metabolism
  • Benzamides / pharmacology*
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / pathology
  • Drug Resistance, Neoplasm / drug effects*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Female
  • HEK293 Cells
  • Humans
  • Indazoles / pharmacology*
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / pathology
  • Male
  • Mice, Inbred NOD
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Models, Biological*
  • Neoplasms / enzymology*
  • Neoplasms / pathology*
  • Pancreatic Neoplasms / diagnostic imaging
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor, trkA / metabolism*


  • Bcl-2-Like Protein 11
  • Benzamides
  • Indazoles
  • Protein Kinase Inhibitors
  • ErbB Receptors
  • Receptor, trkA
  • Mitogen-Activated Protein Kinase Kinases
  • entrectinib