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

Abstract

Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a critical role in cancer progression, metastasis, stem cell maintenance, and therapy resistance. Here, we describe a rationally designed first-in-class inhibitor of LIFR, EC359, which directly interacts with LIFR to effectively block LIF/LIFR interactions. EC359 treatment exhibits antiproliferative effects, reduces invasiveness and stemness, and promotes apoptosis in triple-negative breast cancer (TNBC) cell lines. The activity of EC359 is dependent on LIF and LIFR expression, and treatment with EC359 attenuated the activation of LIF/LIFR-driven pathways, including STAT3, mTOR, and AKT. Concomitantly, EC359 was also effective in blocking signaling by other LIFR ligands (CTF1, CNTF, and OSM) that interact at LIF/LIFR interface. EC359 significantly reduced tumor progression in TNBC xenografts and patient-derived xenografts (PDX), and reduced proliferation in patientderived primary TNBC explants. 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. See related commentary by Shi et al., p.

Interaction of transcription factor AP‐2 gamma with proto‐oncogene PELP1 promotes tumorigenesis by enhancing RET signaling

“…The cell viability of the BC model cells expressing TFAP2C or control shRNA was assessed by using MTT assay as described [24]. For colony formation assays, BC model cells (500 cells per well) were seeded into six‐well plates and are allowed to grow for 14 days as described [24]. The cells were fixed in ice‐cold methanol and stained with 0.5% crystal violet solution.…”

Immunization against leukemia inhibitory factor and its receptor suppresses tumor formation of breast cancer initiating cells in BALB/c mouse

“…Furthermore, ILEI is an oncogenic cytokine that can bind to LIFR and trigger EMT and CSC traits of breast tumors via STAT3 activation 36 . Viswanadhapalli and co-workers discovered a new small molecule, which could inhibit the oncogenic action of LIFR in MBA-MD-231 cells 37 . These findings might introduce LIFR as an immunotherapy target in ER-positive breast tumors and triple-negative breast cancers.…”

GP130 Cytokines in Breast Cancer and Bone

“…These data suggest that the inhibition of STAT3 in the primary site is critical to reducing tumor cell growth, but in distant metastatic sites, such as the bone marrow, STAT3 inactivation could lead to the awakening of dormant tumor cells. In contrast to this, the small molecule inhibitor EC359, which has been shown to directly interact with LIFR to block its interactions with LIF, OSM, CNTF, and CT-1, reduced LIFR-mediated activation of multiple gene targets, STAT3 activity, and downstream target genes, and suppressed TNBC xenograft and PDX tumor growth in vivo [141]. While ER+ breast cancer cell lines were used in the initial screens for LIF and LIFR in these studies, functional studies were all carried out in TNBC cell lines, so it is unclear whether EC359 would have had similar effects on ER+ tumor progression in vivo.…”