7O - Molecular drivers and therapeutic targets for neuroendocrine transformation in lung cancer

Background

Histological transformation from lung adenocarcinoma (LUAD) to an aggressive neuroendocrine (NE) derivative resembling small cell carcinoma (SCLC) is a signature example of lineage plasticity in cancer. NE transformation is the primary mechanism of acquired resistance in up to 14% of EGFR-mutant LUADs. Little is known about the molecular alterations occurring during NE transformation in human tumors. The high prevalence, together with the fact that transformed SCLC has a notably poor prognosis, make in-depth understanding of NE transformation in lung cancer highly clinically relevant and a critical need.

Methods

We performed multi-omic (genomic, transcriptomic, epigenomic and proteomic) characterization of NE transformation in combined LUAD/SCLC histology (n=22); pre-transformation LUADs (n=5) and post-transformation SCLCs (n=3); never-transformed LUADs (n=15); and de novo SCLCs (n=18) clinical specimens. We performed pharmacological inhibition studies in EGFR-mutant patient-derived xenograft (PDX) model.

Results

Our results suggest that NE transformation is primarily driven by transcriptional reprogramming rather than mutational events and indicate that the resulting SCLC retain transcriptomic and methylation profiles of their previous LUAD state. Gene expression and epigenetic profiling showed upregulation of key lineage determining transcription factor like FOXN4, ONECUT2 and POU3F2 during NE transformation. Furthermore, we observed a concurrent suppression of NOTCH signaling, innate immunity; and antigen presentation throughout the process of NE transformation. Pharmacologic inhibition of AKT in combination with osimertinib prevented relapse and NE transformation in an EGFR-mutant patient-derived xenograft model, and inhibition of AKT signaling re-sensitized resistant LUAD tumors to osimertinib.

Conclusions

In this study, we report the first comprehensive multi-omic characterization of LUAD to SCLC transformation in a large cohort of clinical samples. We provide novel insights into molecular drivers and potential therapeutic targets of this NE transformation in lung cancer. Furthermore, our study supports the role of targeting AKT signaling pathway in delaying NE relapse in EGFR-mutant LUAD.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The author.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.