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MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation

Jian Ma1,2,3, Lei Li1,2,3, Bohan Ma1,2,3

  • 1Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.

Nature Communications
|February 29, 2024
PubMed

Insights

MYC amplification causes resistance to CDK4/6 inhibitors (CDK4/6i) in cancers. A new compound, A80.2HCl, degrades MYC, restoring sensitivity to CDK4/6i and reducing tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • CDK4/6 inhibitors (CDK4/6i) are effective against certain cancers like breast cancer.
  • Mechanisms of resistance and broader applications of CDK4/6i remain unclear.

Purpose of the Study:

  • Investigate MYC's role in CDK4/6i resistance.
  • Identify therapeutic strategies to overcome MYC-driven resistance.

Main Methods:

  • Utilized cancer cell lines (bladder, prostate, breast) with varying MYC levels.
  • Assessed the impact of MYC amplification on CDK4/6i sensitivity.
  • Investigated the molecular mechanism of MYC-induced resistance involving KLHL42 and RB1.
  • Screened and evaluated a MYC-degrading compound (A80.2HCl).
  • Performed in vivo tumor growth studies combining CDK4/6i and A80.2HCl.

Main Results:

  • MYC amplification confers intrinsic resistance to CDK4/6i in multiple cancer types.
  • MYC upregulates KLHL42, leading to RB1 degradation and CDK4/6i resistance.
  • The compound A80.2HCl effectively degrades MYC at nanomolar concentrations.
  • A80.2HCl restores RB1 levels and re-sensitizes MYC-amplified cancer cells to CDK4/6i.
  • Combination therapy with CDK4/6i and A80.2HCl significantly inhibits tumor growth in vivo.

Conclusions:

  • MYC amplification is a key mechanism of resistance to CDK4/6 inhibitors.
  • Targeting MYC degradation with compounds like A80.2HCl can overcome this resistance.
  • Combination therapy holds promise for treating MYC-driven cancers resistant to CDK4/6i.

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