G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer

Rui Xiong,Debra A Tonetti,Delita A Thompson,Jiong Zhao,Kendall A Heetderks,Gregory R J Thatcher,Jay C Strum,Christina A Chao,Yeeun Bae,Robert Baldi,John D Norris,Jennifer G Baker,Lauren M Gutgesell,Jessica A Sorrentino,Kaitlyn J Andreano,John E Bisi,Taylor K Desautels,Suzanne E Wardell

doi:10.1007/s10549-020-05575-9

Abstract

PurposeThe combination of targeting the CDK4/6 and estrogen receptor (ER) signaling pathways with palbociclib and fulvestrant is a proven therapeutic strategy for the treatment of ER-positive breast cancer. However, the poor physicochemical properties of fulvestrant require monthly intramuscular injections to patients, which limit the pharmacokinetic and pharmacodynamic activity of the compound. Therefore, an orally available compound that more rapidly reaches steady state may lead to a better clinical response in patients. Here, we report the identification of G1T48, a novel orally bioavailable, non-steroidal small molecule antagonist of ER.MethodsThe pharmacological effects and the antineoplastic mechanism of action of G1T48 on tumors was evaluated using human breast cancer cells (in vitro) and xenograft efficacy models (in vivo).ResultsG1T48 is a potent and efficacious inhibitor of estrogen-mediated transcription and proliferation in ER-positive breast cancer cells, similar to the pure antiestrogen fulvestrant. In addition, G1T48 can effectively suppress ER activity in multiple models of endocrine therapy resistance including those harboring ER mutations and growth factor activation. In vivo, G1T48 has robust antitumor activity in a model of estrogen-dependent breast cancer (MCF7) and significantly inhibited the growth of tamoxifen-resistant (TamR), long-term estrogen-deprived (LTED) and patient-derived xenograft tumors with an increased response being observed with the combination of G1T48 and the CDK4/6 inhibitor lerociclib.ConclusionsThese data show that G1T48 has the potential to be an efficacious oral antineoplastic agent in ER-positive breast cancer.

Highlights

The estrogen receptor (ER/ESR1) is expressed in a majority of breast cancers, and drugs that inhibit ER signaling are the cornerstone of breast cancer pharmacotherapy for ER-positive/HER2-negative disease [1]
G1T48 is similar to fulvestrant in its ability to downregulate the estrogen receptor and inhibit estrogen signaling in breast cancer cells
We evaluated the ER selectivity of G1T48 by assessing its ability to inhibit the transcriptional activity of related steroid hormone receptors androgen receptor (AR), progesterone receptor (PR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) using a cell-based reporter assay

Summary

Introduction

The estrogen receptor (ER/ESR1) is expressed in a majority of breast cancers, and drugs that inhibit ER signaling are the cornerstone of breast cancer pharmacotherapy for ER-positive/HER2-negative disease [1]. Breast Cancer Research and Treatment (2020) 180:635–646 include the Selective Estrogen Receptor Modulator (SERM) tamoxifen that acts as a competitive ER antagonist in the breast, and aromatase inhibitors (AIs) that inhibit aromatase, the enzyme responsible for estrogen production [2, 3]. Mechanisms of resistance to these endocrine therapies include cell cycle dysregulation and activation of alternative growth factor signaling pathways [1]. Genomic alterations in the ER gene itself, including amplification, translocation, and ligand binding domain mutations (most frequently ER-D538G and ER-Y537S) have emerged with AI therapy [1, 8,9,10]

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Results

Conclusion