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Updated: Apr 24, 2026

All-optical Mechanobiology Interrogation of Yes-associated Protein in Human Cancer and Normal Cells using a Multi-functional System
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YAP1 Defines an Emergent, Plastic Population of Relapsed SCLC

C Allison Stewart1, Kavya Ramkumar1, Runsheng Wang1

  • 1Department of Thoracic/Head & Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer
|April 22, 2026
PubMed
Abstract

Insights

YAP1 expression emerges in relapsed small cell lung cancer (SCLC), indicating treatment resistance. These YAP1-positive cells evolve towards large-cell neuroendocrine carcinoma (LCNEC) features, evading therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor known for rapid chemoresistance and poor outcomes.
  • Transcriptional heterogeneity in SCLC leads to distinct subtypes with varying clinical vulnerabilities.
  • YAP1 expression is typically absent in treatment-naïve SCLC but its role in resistance is unclear.

Purpose of the Study:

  • To investigate the emergence and characteristics of YAP1-positive cells in relapsed SCLC.
  • To understand the molecular and cellular changes associated with SCLC treatment resistance.
  • To identify potential therapeutic targets in YAP1-positive SCLC.

Main Methods:

  • Analysis of circulating tumor DNA, circulating tumor cells, and core needle biopsies from SCLC patients and preclinical models.
  • Characterization of YAP1-positive cell populations following resistance to standard-of-care therapies.
  • Comparative analysis of YAP1-positive cells versus treatment-naïve SCLC and LCNEC.

Main Results:

  • A YAP1-positive cell population emerges in SCLC resistant to treatment.
  • These YAP1-positive cells display characteristics of drug-tolerant persisters, including senescence, stemness, and plasticity.
  • YAP1-positive cells undergo a lineage plasticity, shifting from SCLC-like to LCNEC-like features, altering surface target expression.

Conclusions:

  • YAP1 expression is a marker of emergent SCLC treatment resistance.
  • The SCLC to LCNEC-like evolution in YAP1-positive cells contributes to therapeutic evasion.
  • Targeting YAP1 or its downstream pathways may offer new strategies for overcoming SCLC resistance.
Keywords:
Intratumoral heterogeneityPlasticitySCLCYAP1

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