# EGFR-mutant transformed small cell lung cancer harbors intratumoral heterogeneity targetable with MEK inhibitor combination therapy

## TL;DR

EGFR-mutant transformed small cell lung cancer has mixed cell types that respond differently to treatment, and combining MEK inhibitors with chemotherapy could be an effective strategy.

## Contribution

The study identifies intratumoral heterogeneity in EGFR-mutant transformed SCLC and proposes MEK inhibitor combination therapy as a novel treatment approach.

## Key findings

- EGFR-mutant transformed SCLC contains distinct neuroendocrine and non-neuroendocrine cell subsets.
- Non-neuroendocrine cells are selectively sensitive to MEK inhibitors.
- Combining MEK inhibitors with chemotherapy inhibits growth of both cell types in vitro and in vivo.

## Abstract

Small cell lung cancer (SCLC) transformation is an incompletely characterized mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant cancers, limiting development of optimal treatment approaches. Through single-cell RNA sequencing of malignant pleural effusions from patients who underwent SCLC transformation, we identified heterogeneity and diversity, including distinct neuroendocrine (NE) and mesenchymal non-NE cancer cell subsets, which were maintained in patient-derived cell lines. We demonstrate that EZH2 regulates EGFR expression in NE cells where EGFR expression is silenced at baseline. Although neither epigenetic derepression nor exogenous overexpression of mutant EGFR sensitized the cells to EGFR inhibition, non-NE cells exhibited selective sensitivity to MEK inhibitors. Combined MEK inhibitor and chemotherapy effectively inhibited growth of both NE and non-NE cells in vitro and in vivo. Our findings demonstrate that EGFR-mutant SCLC is composed of mixed cell states with distinct therapeutic vulnerabilities and offer a therapeutic strategy to target tumor heterogeneity in highly plastic and treatment-resistant malignancies such as transformed SCLC.

EGFR mutant SCLC comprises mixed cell states with distinct therapeutic vulnerabilities, and MEK inhibitor combination therapy may offer a novel therapeutic strategy to target heterogeneity.