Preclinical Characterization of Hippo pathway inhibition: Insights from Pharmacological and Genetic Studies

The Hippo pathway is an evolutionarily conserved regulator of growth, regeneration, and organ homeostasis, and while its dysregulation is well established in cancer, the effects of inhibiting this pathway on normal tissues are less understood. Here we have systematically investigated the impact of Hippo pathway inhibition by comparing pharmacologic perturbation using a covalent small-molecule TEAD inhibitor (TEADi CMPD1, also known as GNE-8025) with genetic suppression of YAP/TAZ. We identified three key target organs that consistently emerged upon TEAD inhibition: the kidney, as well as the pancreas, and thymus. Across models, both perturbations led to comparable disease phenotypes in these organs, including tubular degeneration in the kidney, acinar atrophy in the pancreas, and lymphoid depletion in the thymus. However, the extent of damage was more pronounced in mice treated with the small-molecule inhibitor, highlighting potential dose and compound specific effects while remaining broadly consistent with the phenotypes observed upon genetic ablation of YAP/TAZ. This highlights the key role of evaluating both genetic and pharmacological perturbations to characterize the phenotypes and potential toxicities when modulating novel targets in oncology. To further investigate the mechanisms underlying pan-TEAD inhibition and kidney related adverse effects, we further characterized this class effect through a comprehensive transcriptomic analysis of the kidney to map the pathways involved in renal response. SignificanceUnderstanding on target toxicities is critical for the safe clinical development of TEAD inhibitors. Here, by integrating pharmacologic TEAD inhibition with genetic suppression by developing a mouse model that characterizes systemic, inducible knockdown of YAP/TAZ, we provide a systematic framework to define the Hippo pathway liabilities in vivo. We identify kidney, pancreas, and thymus as conserved target organs with concomitant phenotypes across both genetic and pharmacological methods, establishing these as pathway driven effects. Importantly, we uncover dose dependent and partially irreversible injury, particularly in kidney and pancreas, alongside mechanistic insight linking TEAD inhibition to aldosterone signaling disruption in kidney. These findings highlight the importance of strategies to identify monitorable, manageable adverse effect to guide clinical translation of TEAD targeting strategies.