YAP1 expression drives chemotherapy resistance in small cell lung cancer

Researchers from The University of Texas MD Anderson Cancer Center have discovered that some cancer cells express the YAP1 protein only after treatment with chemotherapy, allowing them to survive by becoming more invasive and leading to treatment resistance with eventual relapse in patients with small cell lung cancer (SCLC).

The study, published in the Journal of Thoracic Oncology and led by Carl Gay, M.D., Ph.D., associate professor of Thoracic/Head and Neck Medical Oncology, suggests that targeting cells with YAP1 may be a possible strategy to help overcome treatment resistance.

These findings highlight YAP1-expressing cells as biomarkers of chemotherapy resistance in small cell lung cancer. 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."

Carl Gay, M.D., Ph.D., associate professor of Thoracic/Head and Neck Medical Oncology

What is YAP1 and what is its role in small cell lung cancer?

YAP1 is a key activator of signaling pathways that promote cell proliferation and inhibit apoptosis, or cell death. This means it acts as a cancer-promoting oncogene when overactivated.

SCLC is a very aggressive type of lung cancer that initially responds well to chemotherapy but usually becomes resistant, leading to relapse and poor patient outcomes. At least four major SCLC subtypes have different tumor immune microenvironments, meaning they have different sets of cells regulating processes such as tumor initiation, progression, metastasis and treatment response.

Previous studies contended that YAP1 could be a marker for one of the SCLC subtypes, as it shows up in both preclinical models and patient samples following treatment resistance and relapse. This led the researchers to further study its expression in tumors before and after treatment.

What does YAP1 expression mean for patients with relapsed SCLC?

The researchers confirmed that untreated SCLC tumors have little to no YAP1 expression, arguing that YAP1 expression is not a subtype-defining feature in untreated, pure SCLC. Further multi-omics analyses revealed that YAP1-positive cells primarily appear after treatment with chemotherapy, coinciding with the development of resistance and cancer relapse.

In relapse samples, YAP1 expression is often but not always present. However, high YAP1 expression may be a biomarker for chemotherapy-resistant cell populations, highlighting a potential therapeutic target to develop combination therapies.

The authors suggest that further studies using other therapeutic strategies, such as antibody-drug conjugates and T cell engagers, should be examined to see if YAP1 emergence is a common product of treatment resistance.