Mode of action and pharmacogenomic biomarkers for exceptional responders to didemnin B.

Abstract

Modern cancer treatment employs many effective chemotherapeutic agents originally discovered from natural sources. However, a significant challenge currently confronting clinical application is balancing systemic toxicity risk with therapeutic benefit. The cyclic depsipeptide didemnin B has demonstrated impressive anti-cancer activity in preclinical models. Clinical use has been approved but is limited by sparse patient responses combined with toxicity risk and an unclear mechanism of action. From a broad-scale effort to match antineoplastic natural products to their cellular activities, we found that didemnin B selectively induces rapid and wholesale apoptosis through dual inhibition of PPT1 and EEF1A1. Furthermore, empirical discovery of a small panel of exceptional responders to didemnin B allowed generation of a regularized regression model to extract a sparse-feature genetic biomarker capable of predicting sensitivity to didemnin B. This may facilitate patient selection that could enhance and expand therapeutic application of didemnin B against neoplastic disease.