Targeted Inhibition of Leukemia Inhibitory Factor (LIF)/LIFR Axis for the Treatment of Triple-Negative Breast Cancer

Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a critical role in cancer progression and therapy resistance. In this DOD funded project, we developed a first-in-class inhibitor of LIFR, EC359, which binds to LIFR and block LIF/LIFR interactions. EC359 treatment exhibited antiproliferative effects, reduces invasiveness and stemness, and promoted apoptosis in triple-negative breast cancer (TNBC) cell lines. Treatment with EC359 attenuated the activation of LIF/LIFR-driven pathways. EC359 also reduced the viability of therapy resistant TNBC models and enhanced HDAC inhibitors therapy. Further, EC359 significantly reduced tumor progression in TNBC xenografts, and patient-derived xenografts (PDX). EC359 exhibits distinct pharmacologic advantages, including oral bioavailability, and in vivo stability. Collectively, these data support EC359 as a novel targeted therapeutic that inhibits LIFR oncogenic signaling.