INX-315, a selective CDK2 inhibitor, induces cell cycle arrest and senescence in solid tumors
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Date
2024
Authors
Dietrich, C.
Trub, A.
Ahn, A.
Taylor, M.
Ambani, K.
Chan, K.T.
Lu, K.-H.
Mahendra, C.A.
Blyth, C.
Coulson, R.
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Cancer Discovery, 2024; 14(3):446-467
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Catherine Dietrich, Alec Trub, Antonio Ahn, Michael Taylor, Krutika Ambani, Keefe T. Chan, Kun-Hui Lu, Christabella A. Mahendra, Catherine Blyth, Rhiannon Coulson, Susanne Ramm, April C. Watt, Sunil Kumar Matsa, John Bisi, Jay Strum, Patrick Roberts, and Shom Goel
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Abstract
Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring CCNE1 amplification and breast cancers that have acquired resistance to CDK4/6 inhibitors (CDK4/6i). The precise impact of pharmacological inhibition of CDK2 is not known due to the lack of selective CDK2 inhibitors. Here we describe INX-315, a novel and potent CDK2 inhibitor with high selectivity over other CDK family members. Using cell-based assays, patient-derived xenografts, and transgenic mouse models, we show that INX-315 (i) promotes retinoblastoma protein hypo-phosphorylation and therapy-induced senescence (TIS) in CCNE1-amplified tumors, leading to durable control of tumor growth; (ii) overcomes breast cancer resistance to CDK4/6i, restoring cell cycle control whilst re-instating the chromatin architecture of CDK4/6i-induced TIS; and (iii) delays the onset of CDK4/6i resistance in breast cancer by driving deeper suppression of E2F targets. Our results support the clinical development of selective CDK2 inhibitors.
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© 2023 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.