Study defines SCLC subtypes

Study defines small-cell lung cancer subtypes and distinct therapeutic vulnerabilities for each type

Researchers from The University of Texas MD Anderson Cancer Center have developed the first comprehensive framework to classify small-cell lung cancer (SCLC) into four unique subtypes, based on gene expression, and have identified potential therapeutic targets for each type in a study published today in Cancer Cell.

SCLC is known for rapid, aggressive growth and resistance to treatment, which leads to poor outcomes. While recent advances in immunotherapy and targeted therapy have improved survival for non-small cell lung cancer (NSCLC), progress for SCLC has been limited.

“For decades, small-cell lung cancer has been treated as a single disease because the tumors all look similar under the microscope, even though they behave very differently,” said Lauren Averett Byers, M.D., associate professor of Thoracic/Head & Neck Medical Oncology and senior author of the study. “Our study provides a transformative new system to define four major groups of small-cell lung cancer and, for the first time, an avenue for personalized treatment of the second most common type of lung cancer.”

Four major subtypes of SCLC

Although previous research identified three possible subtypes of SCLC based on transcription factors, which indicate whether particular genes are turned “on” or “off,” a large number of SCLC tumors didn’t fit into one of the three groups. Rather than trying to apply a hypothesis to the remaining tumors, Byers’ team took an unbiased bioinformatics approach-letting the data from a large set of SCLC tumor samples speak for itself. This led to a 1,300 gene “signature” that confirmed the three previously observed groups (A, N and P), plus a previously unrecognized fourth group (I) with a unique immune landscape.

The first three groups are defined by activation of the ASCL1 (SCLC-A), NEUROD1 (SCLC-N), and POU2F3 (SCLC-P) genes. The fourth type, SCLC-I, is characterized by an inflamed gene signature with a high expression of multiple immune genes, including significantly greater levels of genes indicating the presence of CD8-positive cytotoxic T cells.