Histone Lysine Demethylase KDM4A as a Therapeutic Target for Small Cell Lung Cancer

Small cell lung cancer (SCLC) arises from neuroendocrine cells within the lung. Along with deletion or loss-of-function RB1 and TP53 mutations, which occur in almost all cases, subsets of SCLC are driven by specific lineage transcription factors including ASCL1, NEUROD1, POU2F3, or YAP1. The expression of various MYC family members leads to further inter-tumor heterogeneity. Despite this heterogeneity in SCLC, the current treatment for SCLC is lineage-transcription-factor-subtype agnostic. Although most patients are initially responsive to first-line etoposide and platin chemotherapy, they soon develop resistance, and no effective second-line therapy is currently available. A recent large NCI screen showed that over 60 SCLC cell line models responded to > 500 investigational drugs in a manner highly correlated with etoposide responses, suggesting that none of these drugs would provide benefits against SCLC beyond those of current chemotherapy. By analyzing publicly available data from shRNA and CRISPR screens in addition to our own RNA-seq expression data, I identified KDM4A as a potential candidate to target in SCLC. To underscore the potential of KDM4A as an anti-SCLC target, I tested the response phenotypes of etoposide and three JmjC KDM inhibitors using a panel of SCLC cell lines representing all the SCLC transcription factor subtypes and found that SCLC responses to JmjC KDM inhibitors did not correlate with their responses to etoposide. Furthermore, I found that upon treatment with the pan-JmjC KDM inhibitor JIB-04, many genes in the ER stress signaling pathways were upregulated in SCLC cell lines, suggesting that this is the mechanistic path leading to SCLC death following Jumonji inhibition. Additional analysis revealed that JIB-04-resistant cells also activated pro-survival pathways such as mTOR to overcome the effects of JIB-04 treatment. I also found that the loss of KDM4A in a SCLC cell line led to slower proliferation and activity in the ER stress signaling pathway. In summary, I identified ...