^
    2ms
    Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle. (PubMed, Nat Commun)
    CRISPR screens identify CDK2 loss as a mediator of resistance to a CDK2 inhibitor, INX-315...These include the depletion of mitotic regulators as well as CDK4/6 inhibitors cooperate with CDK2 inhibition in multiple phases of the cell cycle. Overall, this study underscores two fundamentally distinct features of response to CDK2 inhibitors that are conditioned by tumor context and could serve as the basis for differential therapeutic strategies in a wide range of cancers.
    Journal
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    CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • CCNE1 (Cyclin E1) • CDK1 (Cyclin-dependent kinase 1) • CCNB1 (Cyclin B1)
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    INX-315
    1year
    A Highly Anticipated Selective Therapeutic Agent against CDK2: INX-315. (PubMed, Cancer Discov)
    This agent shows promise in CCNE1-amplified cancers and in CDK4/6 inhibitor-resistant breast cancers. See related article by Dietrich et al., p. 446 (8).
    Journal
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    CCNE1 (Cyclin E1) • CDK2 (Cyclin-dependent kinase 2)
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    CCNE1 amplification
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    INX-315
    over1year
    INX-315, a selective CDK2 inhibitor, induces cell cycle arrest and senescence in solid tumors. (PubMed, Cancer Discov)
    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.
    Journal
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    CCNE1 (Cyclin E1)
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    CCNE1 amplification
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    INX-315
    2years
    INX-315-01: Open-Label Study to Evaluate the Safety, Tolerability, PK, and Efficacy of INX-315 in Patients With Advanced Cancer (clinicaltrials.gov)
    P1/2, N=81, Recruiting, Incyclix Bio | Not yet recruiting --> Recruiting
    Enrollment open • Metastases
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    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • CCNE1 (Cyclin E1)
    |
    HER-2 negative • CCNE1 amplification
    |
    INX-315
    2years
    INX-315-01: Open-Label Study to Evaluate the Safety, Tolerability, PK, and Efficacy of INX-315 in Patients With Advanced Cancer (clinicaltrials.gov)
    P1/2, N=81, Not yet recruiting, Incyclix Bio
    New P1/2 trial • Metastases
    |
    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • CCNE1 (Cyclin E1)
    |
    HER-2 negative • CCNE1 amplification
    |
    INX-315