TROP2 antibody-drug conjugate sacituzumab govitecan (SG) is approved for treatment of advanced breast cancer. However, intrinsic and acquired resistance occur, leading to a need for novel therapies. We hypothesized that antagonists of inhibitor of apoptosis protein (IAP) enhance the activity of SG and its payload. In this preclinical study, we employed breast cancer models, including patient-derived xenografts (PDXs) and cell lines, to conduct combination therapies with SG and IAP inhibitors. In PDXs, birinapant enhanced the antitumor activity of several chemotherapeutics, especially irinotecan, a metabolic precursor of payload SN-38. We subsequently demonstrated that combinations of SG with birinapant or tolinapant had greater antitumor activity and significantly prolonged event-free survival compared with SG alone. In vitro, IAP antagonists significantly synergized with SG on inhibition of cell viability and colony formation, and on apoptosis induction. These findings suggest that SG combination with IAP inhibitors may represent an effective therapeutic strategy for breast cancer.

The role of extrachromosomal DNA (ecDNA) in lung cancer, particularly in subjects who never smoked (LCINS), remains unclear. Examination of over 1200 whole-genome-sequenced lung cancers identified ecDNA in 18.9% of patients. Recurrent amplification of MDM2 and other oncogenes via ecDNA possibly drives a LCINS subset. Tumors harboring ecDNA showed worse overall survival than tumors harboring other focal amplifications. A strong association with whole-genome doubling suggests most ecDNA reflects genomic instability in treatment-naïve lung cancer.

Preclinical studies in transplant tumor models showing high cure rates with combined radiotherapy (RT) and immunotherapy have rarely translated to clinical success, and studies in autochthonous tumor models are limited. We hypothesized that lymphocytes differentially affect RT response in transplant vs autochthonous tumor models. Here, we compared tumor onset and growth delay after 0 or 20 Gy for autochthonous vs transplant soft tissue sarcomas in Rag2-/- mice lacking an adaptive immune system vs immune-intact Rag2+/- mice. While time to tumor onset did not differ between Rag2-/- and Rag2+/- mice in the autochthonous model, transplant tumor onset was significantly slower in immunocompetent mice. No transplant tumors in Rag2-/- mice or autochthonous tumors were cured by RT, whereas 32% of Rag2+/- mice with transplant tumors were cured. These results highlight the importance of including autochthonous tumors as complementary model systems to study the interplay between the immune system and RT response.