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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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Off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their antitumor activity in RAS-driven

Yiming Miao1, Yunpeng Bai1, Jinmin Miao1

  • 1Department of Medicinal Chemistry and Molecular Pharmacology and.

The Journal of Clinical Investigation
|June 6, 2024
PubMed

Insights

SHP2 inhibitors unexpectedly block autophagy, enhancing their anti-cancer effects. This dual action combats RAS/MAPK signaling and resistance, offering new hope for treating cancers like pancreatic and colorectal.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Aberrant RAS/MAPK signaling drives cancer.
  • SHP2 is a key target for RAS/MAPK pathway inhibition.
  • Existing SHP2 inhibitors face adaptive resistance, limiting efficacy.

Purpose of the Study:

  • To investigate off-target effects of SHP2 allosteric inhibitors.
  • To explore the role of autophagy inhibition in SHP2 inhibitor activity.
  • To develop a therapeutic strategy combining on- and off-target effects.

Main Methods:

  • Analysis of SHP2 inhibitor accumulation in cancer cells.
  • Assessment of autophagic flux in response to inhibitors.
  • Evaluation of antitumor activity in preclinical cancer models.
  • Investigation of resistance mechanisms like MAPK rebound.

Main Results:

  • SHP2 inhibitors accumulate in lysosomes and inhibit autophagic flux independently of SHP2.
  • This off-target autophagy inhibition contributes to antitumor activity.
  • Inhibitors with this dual action overcome resistance mechanisms.
  • A therapeutic framework leveraging both on- and off-target effects was demonstrated.

Conclusions:

  • SHP2 allosteric inhibitors possess a previously unrecognized off-target effect on autophagy.
  • This dual inhibition enhances anti-cancer efficacy and overcomes resistance.
  • Harnessing both on- and off-target activities presents a promising therapeutic strategy for RAS/MAPK-driven and resistant cancers.
Keywords:
CancerDrug therapyOncologyPhosphoprotein phosphatasesTherapeutics

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