SHP2 Drives Adaptive Resistance to ERK Signaling Inhibition in Molecularly Defined Subsets of ERK-Dependent Tumors

Cell Rep. 2019 Jan 2;26(1):65-78.e5. doi: 10.1016/j.celrep.2018.12.013.

Abstract

Pharmacologic targeting of components of ERK signaling in ERK-dependent tumors is often limited by adaptive resistance, frequently mediated by feedback-activation of RTK signaling and rebound of ERK activity. Here, we show that combinatorial pharmacologic targeting of ERK signaling and the SHP2 phosphatase prevents adaptive resistance in defined subsets of ERK-dependent tumors. In each tumor that was sensitive to combined treatment, p(Y542)SHP2 induction was observed in response to ERK signaling inhibition. The strategy was broadly effective in TNBC models and tumors with RAS mutations at G12, whereas tumors with RAS(G13D) or RAS(Q61X) mutations were resistant. In addition, we identified a subset of BRAF(V600E) tumors that were resistant to the combined treatment, in which FGFR was found to drive feedback-induced RAS activation, independently of SHP2. Thus, we identify molecular determinants of response to combined ERK signaling and SHP2 inhibition in ERK-dependent tumors.

Keywords: BRAF; ERK signaling; FGFR; MEK; RAS; RTK signaling; SHP2; TNBC; adaptive resistance; targeted therapies; triple-negative breast cancer.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Colonic Neoplasms
  • Drug Resistance, Neoplasm
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • HEK293 Cells
  • HT29 Cells
  • HeLa Cells
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Mice
  • Mice, Nude
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology*
  • Piperidines / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
  • Pyrimidines / pharmacology
  • Signal Transduction
  • Xenograft Model Antitumor Assays

Substances

  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • SHP099
  • Extracellular Signal-Regulated MAP Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11