YAP1 Defines an Emergent, Plastic Population of Relapsed SCLC

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.