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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

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Targeting SHP2 phosphatase in breast cancer overcomes RTK-mediated resistance to PI3K inhibitors

Guus J J E Heynen1, Kamil Lisek2, Regina Vogel2

  • 1Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125, Berlin, Germany. gustaaf.heynen@mdc-berlin.de.

Breast Cancer Research : BCR
|April 2, 2022
PubMed
Abstract

Insights

Combining PI3K and SHP2 inhibitors overcomes resistance in breast cancer models. This dual inhibition blocks tumor cell proliferation and sustains pathway inactivation, offering a promising new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Phosphoinositide 3-kinase (PI3K) signaling is crucial in breast cancer, but resistance to PI3K inhibitors is common.
  • Activated receptor tyrosine kinases often mediate this resistance, reducing PI3K inhibitor efficacy.
  • SHP2 phosphatase is a key mediator in signaling pathways and a potential target for combination therapy.

Purpose of the Study:

  • To investigate the efficacy of combining PI3K and SHP2 inhibitors in PI3K-resistant breast cancer models.
  • To evaluate the impact of dual inhibition on tumor cell proliferation and signaling pathways.

Main Methods:

  • Utilized experimental breast cancer models with acquired and intrinsic PI3K resistance.
  • Employed cell culturing, biochemical assays, and genetic approaches.
  • Assessed tumor cell proliferation and signaling output following PI3K and SHP2 inhibitor treatment.

Main Results:

  • Combination therapy effectively counteracted PI3K resistance mediated by receptor tyrosine kinases.
  • Dual PI3K and SHP2 inhibition suppressed proliferation and sustained PI3K/MAPK pathway inactivation.
  • SHP2 overexpression induced PI3K inhibitor resistance, and SHP2 activation correlated with resistance development.

Conclusions:

  • SHP2 plays a significant role in mediating resistance to PI3K inhibitors in breast cancer.
  • Combination therapy with PI3K and SHP2 inhibitors shows potential for improving breast cancer treatment outcomes.
Keywords:
Breast cancerDrug resistancePI3K and MAPK signalingSHP2Targeted therapy

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