Expression of the YAP1 protein following treatment with chemotherapy is associated with the development of treatment resistance and cancer relapse in patients with small cell lung cancer (SCLC), according to findings from an analysis published in Journal of Thoracic Oncology. The researchers suggested that YAP1-expressing cells characterize a subpopulation of SCLC following treatment where the tumors are more able to evade therapeutic response than other subtypes.
“These findings highlight YAP1-expressing cells as biomarkers of chemotherapy resistance in small cell lung cancer,” said study leader Carl M. Gay, MD, PhD, Associate Professor of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center. “This brings us another step closer to understanding the mechanisms behind why patients continue to relapse so that we can better adapt our diagnostic and therapeutic strategies to improve patient outcomes.”
The researchers also suggested that YAP1 could be an effective target for overcoming treatment resistance.
Background and Study Methods
There are four major transcriptional subtypes of treatment-naive SCLC tumors with clinically distinct variables. YAP1 expression is rarely found in treatment-naive SCLC. Researchers sought to characterize the expression of YAP1 in SCLC tumors before and after treatment.
Researchers analyzed samples from patients with relapsed SCLC who developed resistance to standard-of-care therapies. They examined circulating tumor DNA, circulating tumor cells, and core needle biopsies to assess the tumor immune microenvironment and transcriptional heterogeneity in relapsed patients.
Key Findings
Prior to treatment, SCLC tumors had little to no YAP1 expression. They primarily appeared after treatment with chemotherapy, as confirmed by multi-omics analyses.
The researchers found a population of relapsed SCLC with emergent YAP1-positive cells which coincided with resistance to treatment. The YAP1-positive cells showed characteristics of senescence, stemness, and plasticity that more closely mimicked large-cell neuroendocrine carcinoma. As a result of this transition, the YAP1-positive cells lacked DLL3 and SEZ6 surface targets but were enriched for B7-H3 and TROP2.
They determined that higher YAP1 expression could be a biomarker for a chemotherapy-resistant SCLC subpopulation.
Going forward, the researchers are looking to explore if YAP1 emergence is associated with treatment resistance following other therapeutic strategies, including antibody-drug conjugates and T-cell engagers.
DISCLOSURES: This work was supported by the National Institutes of Health (NIH), the National Cancer Institute (NCI), the Cancer Prevention and Research Institute of Texas (CPRIT), the Department of Defense, the American Lung Association Pierre Massion Lung Cancer Discovery Award, the LUNGevity Foundation, the Neuroendocrine Tumor Research Foundation (NETRF), UT MD Anderson institutional funding, and Rexanna’s Foundation. For full disclosures of the study authors, visit sciencedirect.com.
