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

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

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Purpose: The 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. Methods: The 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). Results: G1T48 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. Conclusions: These data show that G1T48 has the potential to be an efficacious oral antineoplastic agent in ER-positive breast cancer.

Original languageEnglish (US)
Pages (from-to)635-646
Number of pages12
JournalBreast Cancer Research and Treatment
Volume180
Issue number3
DOIs
StatePublished - Apr 1 2020
Externally publishedYes

Keywords

  • CDK4/6 inhibitor
  • Combination therapies
  • Endocrine-resistant breast cancer
  • G1T48
  • Selective estrogen receptor degrader

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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