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Updated: Jan 10, 2026

All-optical Mechanobiology Interrogation of Yes-associated Protein in Human Cancer and Normal Cells using a Multi-functional System
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All-optical Mechanobiology Interrogation of Yes-associated Protein in Human Cancer and Normal Cells using a Multi-functional System

Published on: December 20, 2021

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YAP1 defines an emergent, plastic population of relapsed small cell lung cancer

C Allison Stewart1, Kavya Ramkumar1, Runsheng Wang1

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

Biorxiv : the Preprint Server for Biology
|November 24, 2025
PubMed

Insights

In relapsed small cell lung cancer (SCLC), YAP1-positive cells emerge, exhibiting drug resistance and characteristics of large-cell neuroendocrine carcinoma (LCNEC). These cells evade therapy by altering SCLC surface targets.

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.

Purpose of the Study:

  • To investigate the characteristics of relapsed SCLC after standard-of-care therapy.
  • To identify molecular changes associated with treatment resistance in SCLC.
  • To understand the role of YAP1 in SCLC treatment failure.

Main Methods:

  • Analysis of circulating tumor DNA, circulating tumor cells, and core needle biopsies from SCLC patients and preclinical models.
  • Comparative analysis of YAP1-positive and YAP1-negative SCLC cells.
  • Assessment of cellular characteristics including senescence, stemness, and plasticity.

Main Results:

  • A YAP1-positive cell population emerges in relapsed SCLC, correlating with treatment resistance.
  • YAP1-positive cells display characteristics of drug-tolerant persister cells, including senescence, stemness, and plasticity.
  • These cells evolve from SCLC-like to large-cell neuroendocrine carcinoma (LCNEC)-like, altering expression of surface targets like DLL3, SEZ6, B7-H3, and TROP2.

Conclusions:

  • YAP1 expression is associated with the emergence of treatment resistance in SCLC.
  • YAP1-positive cells represent a tenacious subpopulation that can evade therapeutic responses by adopting LCNEC features.
  • This YAP1-driven evolution highlights a mechanism of therapeutic resistance in SCLC.
Keywords:
SCLCYAP1intratumoral heterogeneityplasticity

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