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Tumor Cell Spatial Organization Directs EGFR/RAS/RAF Pathway Primary Therapy Resistance through YAP Signaling

Rachel Nakagawa1, Andrew Beardsley1,2,3, Sophia Durney1

  • 1Department of Cell & Tissue Biology, University of California, San Francisco, CA, USA.

Biorxiv : the Preprint Server for Biology
|October 10, 2024
PubMed

Insights

Non-small cell lung cancer (NSCLC) cells show resistance to targeted therapies via YAP activation, a non-genetic mechanism dependent on culture context. This finding is crucial for understanding EGFR and KRAS therapy resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Cell Biology

Background:

  • Non-small cell lung cancers (NSCLC) with EGFR or KRAS mutations often develop resistance to targeted therapies.
  • Mechanisms driving acute resistance to initial pathway inhibition are not fully understood.

Purpose of the Study:

  • To investigate the spatial and culture-specific mechanisms of acute resistance to EGFR (EGFRi) and KRASG12C (G12Ci) pathway inhibition in NSCLC.
  • To identify non-genetic resistance mechanisms to targeted therapies.

Main Methods:

  • Utilized in vivo tumor xenografts and in vitro NSCLC cell cultures (monolayer and 3D spheroids).
  • Administered EGFR inhibitors (EGFRi) and analyzed YAP nuclear localization and activity.
  • Assessed cell cycle arrest and cell death in response to inhibitors.
  • Genetically modulated YAP expression (YAPS127A mutant).

Main Results:

  • EGFR mutant xenografts showed significant shrinkage (>90%) with EGFRi, with residual cells exhibiting increased nuclear YAP.
  • In vitro, EGFRi induced cell cycle arrest in monolayer cultures but cell death in 3D spheroids.
  • Differential YAP nuclear localization and activity were observed based on culture conditions.
  • Forced expression of YAPS127A conferred partial resistance to EGFR-mediated cell death in spheroids.

Conclusions:

  • YAP activation in monolayer cultures represents a non-genetic mechanism of acute resistance to EGFR/KRAS/BRAF pathway inhibitors.
  • Culture context (monolayer vs. spheroid) influences cellular response and models distinct stages of cancer progression and resistance.
  • Understanding YAP's role is critical for developing strategies to overcome therapy resistance in NSCLC.
Keywords:
ARS-1620BRAFV600EEGFRKRASG12CNon-small cell lung cancer (NSCLC)afatinibmonolayerosimertinibspheroidvemurafenib

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