Strategies to Target Chemoradiotherapy Resistance in Small Cell Lung Cancer

Simple Summary Small cell lung cancer (SCLC) is a deadly cancer that is treated by chemo- and radiotherapy, which work by damaging DNA. However, most SCLC patients will develop resistance to these treatments, resulting in a poor outlook with few effective treatment options available. This review summarizes our understanding of the causes of treatment resistance and the treatments which have been studied to overcome resistance. While there is still much to be understood, new methods being developed may improve our ability to study this disease and find effective treatments.Abstract Background: Small cell lung cancer (SCLC) is a lethal form of lung cancer with few treatment options and a high rate of relapse. While SCLC is initially sensitive to first-line DNA-damaging chemo- and radiotherapy, relapse disease is almost universally therapy-resistant. As a result, there has been interest in understanding the mechanisms of therapeutic resistance in this disease. Conclusions: Progress has been made in elucidating these mechanisms, particularly as they relate to the DNA damage response and SCLC differentiation and transformation, leading to many clinical trials investigating new therapies and combinations. Yet there remain many gaps in our understanding, such as the effect of epigenetics or the tumor microenvironment on treatment response, and no single mechanism has been found to be ubiquitous, suggesting a significant heterogeneity in the mechanisms of acquired resistance. Nevertheless, the advancement of techniques in the laboratory and the clinic will improve our ability to study this disease, especially in patient populations, and identify methods to surmount therapeutic resistance.