TY - JOUR
T1 - G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer
AU - Andreano, Kaitlyn J.
AU - Wardell, Suzanne E.
AU - Baker, Jennifer G.
AU - Desautels, Taylor K.
AU - Baldi, Robert
AU - Chao, Christina A.
AU - Heetderks, Kendall A.
AU - Bae, Yeeun
AU - Xiong, Rui
AU - Tonetti, Debra A.
AU - Gutgesell, Lauren M.
AU - Zhao, Jiong
AU - Sorrentino, Jessica A.
AU - Thompson, Delita A.
AU - Bisi, John E.
AU - Strum, Jay C.
AU - Thatcher, Gregory R.J.
AU - Norris, John D.
N1 - Funding Information:
This work was supported by a sponsored research grant from G1 Therapeutics. The authors would like to thank the McDonnell laboratory for providing the space to perform the experiments and for topical and intellectual discussions about the research. The authors would also like to think Alexander Yllanes for his technical assistance.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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.
AB - 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.
KW - CDK4/6 inhibitor
KW - Combination therapies
KW - Endocrine-resistant breast cancer
KW - G1T48
KW - Selective estrogen receptor degrader
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U2 - 10.1007/s10549-020-05575-9
DO - 10.1007/s10549-020-05575-9
M3 - Article
C2 - 32130619
AN - SCOPUS:85081597581
SN - 0167-6806
VL - 180
SP - 635
EP - 646
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 3
ER -