Targeting DNA Damage in SCLC

SCLC accounts for 15% of lung cancer worldwide. Characterised by early dissemination and rapid development of chemo-resistant disease, less than 5% of patients survive 5 years. Despite 3 decades of clinical trials there has been no change to the standard platinum and etoposide regimen for first line treatment developed in the 1970's. The exceptionally high number of genomic aberrations observed in SCLC combined with the characteristic rapid cellular proliferation results in accumulation of DNA damage and genomic instability. To flourish in this precarious genomic context, SCLC cells are reliant on functional DNA damage repair pathways and cell cycle checkpoints. Current cytotoxic drugs and radiotherapy treatments for SCLC have long been known to act by induction of DNA damage and the response of cancer cells to such damage determines treatment efficacy. Recent years have witnessed improved understanding of strategies to exploit DNA damage and repair mechanisms in order to increase treatment efficacy. This review will summarise the rationale to target DNA damage response in SCLC, the progress made in evaluating novel DDR inhibitors and highlight various ongoing challenges for their clinical development in this disease.

Keywords

CHLC ONC Aurora Kinases/therapeutic use Azepines/therapeutic use Benzimidazoles/therapeutic use Carbolines/therapeutic use Cell Cycle Checkpoints/drug effects Cell Cycle Checkpoints/genetics Cell Proliferation/drug effects Cell Proliferation/genetics Cytotoxins/therapeutic use DNA Damage/drug effects DNA Damage/genetics DNA Repair Etoposide/therapeutic use Genomic Instability/drug effects Genomic Instability/genetics Heterocyclic Compounds, 4 or More Rings/therapeutic use Lung Neoplasms/drug therapy Lung Neoplasms/genetics Molecular Targeted Therapy/methods Phthalazines/therapeutic use Piperazines/therapeutic use Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use Protein Kinase Inhibitors/therapeutic use Pyrimidines/therapeutic use Rad51 Recombinase/antagonists & inhibitors Rad51 Recombinase/therapeutic use Small Cell Lung Carcinoma/drug therapy Small Cell Lung Carcinoma/genetics