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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genomics

Background:

• Small cell lung cancer (SCLC) transformation is a resistance mechanism to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant cancers.
• This transformation limits effective treatment strategies for these patients.

Purpose of the Study:

• To investigate the heterogeneity and therapeutic vulnerabilities of SCLC transformation.
• To identify potential therapeutic strategies targeting mixed cell states in transformed SCLC.

Main Methods:

• Single-cell RNA sequencing of malignant pleural effusions from patients with SCLC transformation.
• Establishment and analysis of patient-derived cell lines.
• In vitro and in vivo experiments evaluating drug sensitivity.

Main Results:

• Identified distinct neuroendocrine (NE) and mesenchymal non-NE cancer cell subsets within transformed SCLC.
• EZH2 regulates EGFR expression in NE cells; neither epigenetic changes nor EGFR overexpression sensitized cells to EGFR inhibition.
• Non-NE cells showed selective sensitivity to MEK inhibitors.
• Combined MEK inhibitor and chemotherapy effectively inhibited both NE and non-NE cells.

Conclusions:

• EGFR-mutant SCLC exhibits mixed cell states with differential therapeutic vulnerabilities.
• A combination therapy of MEK inhibitors and chemotherapy is effective against both NE and non-NE cells in transformed SCLC.
• This strategy holds promise for treating highly plastic and treatment-resistant malignancies.