INX-315

P1/2, N=150, Recruiting, Incyclix Bio | N=90 --> 150

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.

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).

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.

P1/2, N=81, Recruiting, Incyclix Bio | Not yet recruiting --> Recruiting

P1/2, N=81, Not yet recruiting, Incyclix Bio