Molecular Determinants of Response and Rational Drug Combinations for Antibody-Drug Conjugates (ADCs) with Topoisomerase I (TOP1) Inhibitor Payloads.

Here we describe the different TOP1 poisons used a "payload" for tumor-targeted anticancer therapies in comparison with the widely used first generation TOP1 poisons: Topotecan, Irinotecan and Belotecan. We review the determinants of response to tumor-targeted TOP1 poison inhibitors (TTTis) as candidate companion diagnostic (Dx) biomarkers for precision medicine and patient selection, such as high expression of surface epitopes for ADCs (Antibody Drug Conjugates), high tumor proliferation (Ki67), Schlafen 11 (SLFN11) expression, homologous recombination deficiencies (HRD/BRCAness) and expression of drug efflux transporters such as (BCRP (MXR) encoded by ABCG2. We also summarize the mechanistic rationale for combining TTTis with small molecule inhibitors of poly(ADPribose) polymerase (PARP), ATR (Ataxia Telangiectasia and Rad3-related), CHK1 (Checkpoint Kinase 1) and ATM (Ataxia Telangiectasia Mutated).