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A Kinome-Wide Synthetic Lethal CRISPR/Cas9 Screen Reveals That mTOR Inhibition Prevents Adaptive Resistance to

Yusuke Goto1, Keiichi Koshizuka1, Toshinori Ando1,2

  • 1Moores Cancer Center, University of California San Diego, La Jolla, California.

Cancer Research Communications
|July 2, 2024
PubMed

Insights

Combining mTOR inhibitors with CDK4/6 inhibitors like palbociclib shows promise for treating head and neck squamous cell carcinoma. This combination therapy may overcome resistance to CDK4/6 inhibitors by targeting cyclin E1 expression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Head and neck squamous cell carcinoma (HNSCC) often involves alterations in cell cycle regulators like p16INK4A and cyclin D1.
  • While PI3K/mTOR pathway activation is common in HNSCC, mTOR inhibitors (mTORi) show limited efficacy in advanced stages.
  • CDK4/6 inhibitors have modest clinical effects in HNSCC, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To identify synthetic lethal targets for mTOR inhibitors in HNSCC.
  • To evaluate the synergistic potential of combining mTOR inhibitors with CDK4/6 inhibitors in HNSCC.
  • To elucidate the mechanisms underlying acquired resistance to CDK4/6 inhibitors and how mTOR inhibitors can overcome it.

Main Methods:

  • A kinome-wide CRISPR/Cas9 screen was employed to identify synthetic lethal targets of mTOR inhibitors.
  • In vitro and in vivo studies were conducted using HNSCC-derived cells to assess the combination of mTORi and palbociclib.
  • Mechanistic studies investigated the role of cyclin E1 (CCNE1) expression and its regulation by mTORi and palbociclib.

Main Results:

  • Cell-cycle inhibition was identified as a synthetic lethal target for mTOR inhibitors.
  • The combination of mTORi and palbociclib demonstrated strong synergistic effects in HNSCC models.
  • mTOR inhibitors were found to inhibit the adaptive increase in CCNE1 expression induced by palbociclib, thereby reverting resistance.

Conclusions:

  • Combining mTOR inhibitors with palbociclib offers a promising multimodal therapeutic strategy for HNSCC.
  • This combination therapy can overcome acquired resistance to palbociclib by targeting CCNE1 translation.
  • Targeting both mTOR and CDK4/6 pathways presents a potential approach to halt HNSCC progression and resistance.

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