Related Experiment Video

Updated: Jul 8, 2025

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
11:32

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter

Published on: March 27, 2020

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All Roads Lead to Rome: YAP/TAZ Activity Influences Efficacy of KRASG12C Inhibitors

Christian W Johnson1, Kevin M Haigis1,2

  • 1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Cancer Research
|December 15, 2023
PubMed

Insights

Direct KRASG12C inhibitors are promising cancer treatments. Research shows combining them with YAP/TAZ inhibition can overcome resistance and extend treatment response in lung, colorectal, and pancreatic cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Direct inhibitors targeting KRASG12C mutations represent a significant advancement in cancer therapy.
  • Enhancing response rates and overcoming resistance to KRASG12C inhibitors remain critical challenges in oncology.

Purpose of the Study:

  • To investigate mechanisms of resistance to KRASG12C inhibitors across different cancer types.
  • To identify novel therapeutic strategies for improving efficacy of KRASG12C-targeted therapies.

Main Methods:

  • Utilized CRISPR-based knockout screens to identify genes and pathways modulating KRASG12C inhibitor activity.
  • Validated identified resistance mechanisms in lung, colorectal, and pancreatic cancer models.
  • Assessed the therapeutic potential of combining KRASG12C and YAP/TAZ inhibition in preclinical xenograft models.

Main Results:

  • Identified multiple genes and pathways conferring resistance to KRASG12C inhibitors.
  • Convergent finding across three independent studies: YAP/TAZ pathway activation is a common resistance mechanism.
  • Combined inhibition of KRASG12C and YAP/TAZ significantly extended tumor response to KRASG12C inhibitors, although complete regression was not observed.

Conclusions:

  • YAP/TAZ pathway activation is a key determinant of resistance to KRASG12C inhibitors in various cancers.
  • Co-targeting KRASG12C and YAP/TAZ pathways offers a promising strategy to enhance therapeutic responses and overcome resistance.
  • Further investigation into combination therapies is warranted to improve outcomes for patients with KRASG12C-mutated cancers.

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