Abstract
BACKGROUND AND OBJECTIVE: Small cell lung cancer (SCLC) and Ewing's sarcoma (ES) at the disseminated stage are not amenable to therapy and have a dismal prognosis with low survival rates. Despite representing different tumor entities, treatment for both malignancies relies on cytotoxic chemotherapy that has not considerably changed for the past decades. The genomic background has been extensively studied and found to comprise inactivation of p53 and RB1 in case of SCLC and EWSR1/FLI1 rearrangement in case of ES resulting in aggressive tumors in adults with heavy tobacco consumption and as bone tumor in juveniles, respectively. New therapeutic modalities are urgently needed to improve the outcomes of both tumor entities, especially in patients with metastatic disease or recurrences. This review summarizes the common cell biologic and clinical characteristics of difficult-to-treat SCLC and ES and discusses their refractoriness and options to improve the therapeutic efficacy. METHODS: PubMed and Euro PMC were searched from January 1(st), 2012 to January 16(th), 2022 using the following key words: "SCLC", "Ewing´s sarcoma", "Genomics" and "Chemoresistance" as well as own work. KEY CONTENT AND FINDINGS: Therapy of SCLC and ES involves the use of undirected cytotoxic drugs in multimodal chemotherapy and administration of topotecan for 2(nd) line SCLC regimens. Despite highly aggressive chemotherapies, outcomes are dismal for patients with disseminated tumors. A host of unrelated drugs and targeted therapeutics have failed to result in progress for the patients and the underlying mechanisms of chemoresistance are still not clear. Identification of chemoresistance-reversing modulators in vitro and patient-derived xenografts of SCLC and ES has not translated into new therapies. CONCLUSIONS: The global chemoresistance of SCLC and ES may be explained by physiological resistance at the tumor level and formation of larger spheroids that contain quiescent and hypoxic tumor cells in regions that occlude therapeutics. This type of chemoresistance is difficult to overcome and prevent the accumulation of effective drug concentration at the tumor cell level to a significant degree leaving therapeutic interventions of any kind ineffective.