INX-315, a selective CDK2 inhibitor, induces cell cycle arrest and senescence in solid tumors

Author:

Dietrich Catherine1ORCID,Trub Alec2ORCID,Ahn Antonio1ORCID,Taylor Michael3ORCID,Ambani Krutika1ORCID,Chan Keefe T.4ORCID,Lu Kun-Hui5ORCID,Mahendra Christabella A.1ORCID,Blyth Catherine1ORCID,Coulson Rhiannon3ORCID,Ramm Susanne5ORCID,Watt April C.1ORCID,Matsa Sunil Kumar6ORCID,Bisi John2ORCID,Strum Jay7ORCID,Roberts Patrick7ORCID,Goel Shom8ORCID

Affiliation:

1. University of Melbourne, Australia

2. Incyclix Bio, Durham, NC, United States

3. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

4. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

5. Peter MacCallum Cancer Centre, Melbourne, Australia

6. Ayurveda Molecular Modeling, India

7. Incyclix Bio, United States

8. University of Melbourne, Melbourne, VIC, Australia

Abstract

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.

Publisher

American Association for Cancer Research (AACR)

Subject

Oncology

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