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Supplementary Figures 1-14 from INX-315, a Selective CDK2 Inhibitor, Induces Cell Cycle Arrest and Senescence in Solid Tumors

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posted on 2024-03-01, 11:40 authored by 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, Shom Goel

Supplementary Figure 1: Characterization of INX-315. Supplementary Figure 2: Effect of INX-315 and PF-07104091 on viability of cancer and non-malignant cell lines. Supplementary Figure 3: Effect of INX-315 on cell cycle in CCNE1-amplified cancer cell lines. Supplementary Figure 4: Further characterization of the effects of INX-315 in in vitro and in vivo models of CCNE1-amplified cancer. Supplementary Figure 5: Effects of INX-315 treatment on gene expression in models of CCNE1amplified ovarian carcinoma. Supplementary Figure 6: Characterization of CDK4/6 inhibitor-resistant cell lines. Supplementary Figure 7: Response of CDK4/6 inhibitor-resistant breast cancer cells to INX-315 and PF-07104091. Supplementary Figure 8: Effects of INX-315 and PF-07104091 on CDK4/6 inhibitor-resistant breast cancer cells. Supplementary Figure 9: Impact of INX-315 +/- continued CDK4/6 inhibition in CDK4/6 inhibitorresistant breast cancer cells. Supplementary Figure 10: Characterization of a new mouse model of acquired CDK4/6 inhibitor resistance. Supplementary Figure 11: Effect of INX-315 on expression of senescence-related genes in CDK4/6 inhibitor-resistant breast cancer cells. Supplementary Figure 12: Epigenomic and transcriptomic features of INX-315 induced senescence in CDK4/6 inhibitor-resistant breast cancer. Supplementary Figure 13: Impact of INX-315 treatment of CDK4/6 inhibitor resistant breast cancer on expression of apoptosis and differentiation-related genes. Supplementary Figure 14: Impact of co-inhibition of CDK2 and CDK4/6 on cell cycle and development of CDK4/6 inhibitor resistance in breast cancer cells.

Funding

Snow Medical Research Foundation

National Health and Medical Research Council of Australia

Mark Foundation For Cancer Research (The Mark Foundation for Cancer Research)

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ARTICLE 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 pharmacologic 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 (PDX), and transgenic mouse models, we show that INX-315 (i) promotes retinoblastoma protein hypophosphorylation 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 while reinstating 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. INX-315 is a novel, selective inhibitor of CDK2. Our preclinical studies demonstrate activity for INX-315 in both CCNE1-amplified cancers and CDK4/6i–resistant breast cancer. In each case, CDK2 inhibition induces cell cycle arrest and a phenotype resembling cellular senescence. Our data support the development of selective CDK2 inhibitors in clinical trials.See related commentary by Watts and Spencer, p. 386.This article is featured in Selected Articles from This Issue, p. 384

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    Cancer Discovery

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    Keywords

    Breast CancerCell CycleCell cycle checkpointsCell Death And SenescenceDrug MechanismsCell cycle mechanisms of anticancer drug actionGastrointestinal CancersStomach cancerGynecological CancersSmall Molecule AgentsKinase inhibitorsTranslational Research

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