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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>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\u2013resistant 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.<\/jats:p>\n                    <jats:p>See related commentary by Watts and Spencer, p. 386.<\/jats:p>\n                    <jats:p>This article is featured in Selected Articles from This Issue, p. 384<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-23-0954","type":"journal-article","created":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T08:14:15Z","timestamp":1701677655000},"page":"446-467","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":134,"title":["INX-315, a Selective CDK2 Inhibitor, Induces Cell Cycle Arrest and Senescence in Solid Tumors"],"prefix":"10.1158","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3347-0639","authenticated-orcid":false,"given":"Catherine","family":"Dietrich","sequence":"first","affiliation":[{"name":"1Sir Peter MacCallum Department of Oncology, The University of 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