Deciphering the Role of Neuroendocrine Transcript Expression in the Efficacy of LSD1 Inhibitor RG6016 for Small Cell Lung Cancer

Small cell lung cancer (SCLC) is a severe type of lung cancer, accounting for 15% of lung tumors and characterized by rapid progression and poor treatment options, with a survival rate in refractory cases usually under one year. A recent study by Mohammed et al. indicated that targeting epigenetic regulation through Lysine Specific Demethylase-1 (LSD1) could be a promising therapeutic strategy for SCLC. RG6016, an LSD1 inhibitor, has shown efficacy in both laboratory and animal models of SCLC.

In this research, the team identified a distinctive gene expression profile linked to neuroendocrine characteristics that can predict the response to RG6016 in SCLC cell lines. RG6016 was tested on 19 SCLC cell lines, demonstrating significant activity, particularly in a subset of these lines. The study found that classic SCLC cell lines were more responsive to RG6016 than variant ones, with a statistically significant difference (p-value 0.0055). Out of 11 classic SCLC cell lines, nine were sensitive to RG6016, while seven out of eight variant cell lines were not affected by the treatment.

The differential gene expression analysis highlighted ASCL1, a transcription factor crucial for the development of pulmonary neuroendocrine cells and previously identified as necessary for the survival of most SCLCs. ASCL1, along with other neuroendocrine markers DDC and GRP, were among the top differentially expressed genes. Additionally, the study discovered that some SCLC cell lines resistant to RG6016 had c-MYC amplifications, indicating a possible resistance mechanism.

The researchers established an RG6016 response gene expression pattern that correlates well with growth inhibition, using baseline expression of neuroendocrine transcripts and c-MYC amplification status. This pattern was also found to have a strong correlation between in vitro and in vivo responses. For instance, the cell line NCI-H510A, which was positive for the response signature, had its xenograft growth inhibited by RG6016 treatment, while the negative NCI-H526 xenografts were not affected.

The study suggests that the gene expression signature responsive to RG6016 could potentially be used to identify patients who are more likely to benefit from LSD1-targeted therapies. The research was presented at the 107th Annual Meeting of the American Association for Cancer Research by Francesca Milletti and colleagues, and published in Cancer Research 2016;76(14 Suppl):Abstract nr 4708.