EC359: A First-in-Class Small-Molecule Inhibitor for Targeting Oncogenic LIFR Signaling in Triple-Negative Breast Cancer

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Leukemia inhibitory factor receptor (LIFR) and its ligand LIF are implicated in cancer progression, metastasis, stemness, and therapy resistance.
• Targeting LIFR presents a potential therapeutic strategy for various cancers, particularly triple-negative breast cancer (TNBC).

Purpose of the Study:

• To develop and characterize a novel, first-in-class inhibitor of LIFR, named EC359.
• To evaluate the efficacy of EC359 in preclinical models of triple-negative breast cancer (TNBC).

Main Methods:

• Rational design and synthesis of EC359, a direct LIFR inhibitor.
• In vitro studies using TNBC cell lines to assess antiproliferative, anti-invasive, stemness, and apoptotic effects.
• In vivo studies using TNBC xenografts and patient-derived xenografts (PDX) to evaluate tumor progression.
• Pharmacokinetic and pharmacodynamic assessments of EC359.

Main Results:

• EC359 effectively blocks LIF/LIFR interactions and downstream signaling pathways (STAT3, mTOR, AKT).
• EC359 demonstrated significant antiproliferative, anti-invasive, and pro-apoptotic effects in TNBC cell lines.
• EC359 reduced tumor progression in TNBC xenografts and PDX models, and decreased proliferation in primary TNBC explants.
• EC359 showed oral bioavailability and in vivo stability.

Conclusions:

• EC359 is a potent, orally bioavailable inhibitor of LIFR signaling with significant preclinical anti-cancer activity in TNBC.
• EC359 represents a promising targeted therapeutic agent for LIFR-driven cancers.
• Targeting LIFR with EC359 offers a novel strategy to overcome challenges in cancer progression and therapy resistance.