PARP1 and EZH2 may be useful therapeutic targets in small cell lung cancer (SCLC), based on newly discovered molecular differences between this disease and non-small cell lung cancer (NSCLC).
A highly lethal cancer with a 5-year survival rate of less than 10%, SCLC is more aggressive than NSCLC and distinct from NSCLC in its metastatic potential and treatment response, explained Lauren Averett Byers, MD, and colleagues in Cancer Discovery, a journal of the American Association for Cancer Research (AACR). Byers, an assistant professor of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston, and team profiled SCLCs to identify new therapeutic agents for persons with these cancers. To date, no molecularly targeted agents have prolonged survival in such patients. According to an AACR statement, persons with SCLCs initially respond to chemotherapy, but almost all experience disease recurrence within a few months.
Byers’ group examined the expression of proteins in key signaling pathways known to drive cancer growth. The data revealed fundamental differences in the patterns of pathway activation in SCLCs and in NSCLCs. In SCLC, proteins that were present at higher levels included several DNA repair proteins such as PARP, and a protein involved in cancer stem cell renewal known as EZH2.
Two PARP inhibitors were then tested on SCLC cell lines alone and in combination with the chemotherapeutic agents cisplatin and etoposide or with another common chemotherapy drug, irinotecan. The PARP inhibitors slowed the growth of SCLC cells, but not non-neuroendocrine NSCLC cells. In addition, levels of PARP1 expression directly correlated with PARP inhibitor sensitivity.