SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models

Cancer Discov. 2018 Oct;8(10):1237-1249. doi: 10.1158/2159-8290.CD-18-0444. Epub 2018 Jul 25.


Adaptive resistance to MEK inhibitors (MEKi) typically occurs via induction of genes for different receptor tyrosine kinases (RTK) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 (PTPN11) is required for RAS/ERK pathway activation by most RTKs and might provide a common resistance node. We found that combining the SHP2 inhibitor SHP099 with a MEKi inhibited the proliferation of multiple cancer cell lines in vitro PTPN11 knockdown/MEKi treatment had similar effects, whereas expressing SHP099 binding-defective PTPN11 mutants conferred resistance, demonstrating that SHP099 is on-target. SHP099/trametinib was highly efficacious in xenograft and/or genetically engineered models of KRAS-mutant pancreas, lung, and ovarian cancers and in wild-type RAS-expressing triple-negative breast cancer. SHP099 inhibited activation of KRAS mutants with residual GTPase activity, impeded SOS/RAS/MEK/ERK1/2 reactivation in response to MEKi, and blocked ERK1/2-dependent transcriptional programs. We conclude that SHP099/MEKi combinations could have therapeutic utility in multiple malignancies.Significance: MEK inhibitors show limited efficacy as single agents, in part because of the rapid development of adaptive resistance. We find that SHP2/MEK inhibitor combinations prevent adaptive resistance in multiple cancer models expressing mutant and wild-type KRAS. Cancer Discov; 8(10); 1237-49. ©2018 AACR. See related commentary by Torres-Ayuso and Brognard, p. 1210 This article is highlighted in the In This Issue feature, p. 1195.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Humans
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics*
  • Xenograft Model Antitumor Assays


  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinase Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Ptpn11 protein, mouse