Abstract 176P
Background
Lineage plasticity, the ability to transdifferentiate among distinct phenotypic identities, facilitates therapeutic resistance in multiple cancers. In lung adenocarcinomas (LUADs), this phenomenon includes small cell and squamous cell (LUSC) histologic transdifferentiation in the context of acquired resistance to targeted inhibition of driver mutations. The incidence of transdifferentiation into squamous carcinoma in EGFR mutant tumors occurs in up to 9% of cases relapsed on osimertinib and has been associated with poor prognosis. The paucity of well-annotated pre- and post-transdifferentiation clinical samples has precluded the performance of informative molecular analyses: little is known about the molecular mechanisms leading to this histological transition.
Methods
We performed detailed genomic (whole-exome sequencing), epigenomic, transcriptomic (RNAseq), proteomic (antibody arrays), and single-cell RNAseq and ATACseq characterization. Clinical findings were validated in preclinical models including cell lines and patient-derived xenograft treatments.
Results
Our results suggest that LUSC transdifferentiation is primarily driven by transcriptional reprogramming rather than mutational events, and indicate that the resulting squamous tumors retain transcriptomic and methylation profiles of their previous LUAD state. We observed coordinated upregulation of PI3 K/AKT, MYC, and PRC2 pathway genes in the LUSC component of mixed histology tumors. Concurrent activation of PI3 K/AKT and MYC-induced squamous features in EGFR-mutant LUAD preclinical models, further augmented under the selective pressure of osimertinib. Pharmacologic inhibition of EZH1/2 in combination with osimertinib prevented relapse and squamous transdifferentiation in an EGFR-mutant PDX model, and inhibition of EZH1/2 or PI3 K/AKT signaling re-sensitized resistant transdifferentiated LUSC tumors to osimertinib.
Conclusions
Our findings provide the first comprehensive molecular characterization of LUSC transdifferentiation, suggesting putative drivers and promising therapeutic targets to constrain or prevent lineage plasticity in this setting.
Legal entity responsible for the study
The author.
Funding
Has not received any funding.
Disclosure
The author has declared no conflicts of interest.