Cyclin-dependent kinase 2 (CDK2) inhibitors and others novel CDK inhibitors (CDKi) in breast cancer: clinical trials, current impact, and future directions

• Published in: Critical reviews in oncology/hematology 2024-04, Vol.196, p.104324-104324, Article 104324
• Main Authors: Gerosa, Riccardo, De Sanctis, Rita, Jacobs, Flavia, Benvenuti, Chiara, Gaudio, Mariangela, Saltalamacchia, Giuseppe, Torrisi, Rosalba, Masci, Giovanna, Miggiano, Chiara, Agustoni, Francesco, Pedrazzoli, Paolo, Santoro, Armando, Zambelli, Alberto
• Format: Article
• Language: English
• Subjects: Breast cancer (BC); Cyclin-dependent; Cyclin-dependent kinase 2 inhibitor (CDK2i); Cyclindependent; Kinase 2/4/6 inhibitor (CDK2/4/6i); Kinase 4 inhibitor (CDK4i); Metastatic breast cancer (mBC); Pan-Cyclin-dependent kinase inhibitor (Pan-CDKi)
• ISSN: 1040-8428; 1879-0461
• DOI: 10.1016/j.critrevonc.2024.104324

Aberrant cyclin-dependent kinase 2 (CDK2) activation has been identified as a main resistance mechanism to CDK4/6 inhibition in hormone-receptor positive (HR+) breast cancer. Additionally, consistent preclinical evidence states its crucial role in MYC and CCNE1 overexpressed cancer survival, such as triple-negative breast cancers (TNBC), thus representing an appealing and relatively unexplored target treatment opportunity. Despite emerging initial results of novel CDK2 inhibitors (CDK2i) activity, a comprehensive outcomes collection is currently absent from the scientific literature. We aim to provide an overview of ongoing clinical trials involving CDK2i in the context of metastatic breast cancer (mBC), either as monotherapy or in combination with other agents. The review extends beyond CDK2i to encompass novel emerging CDK4 inhibitors, combined CDK2/4/6 inhibitors, and the well-known pan-CDK inhibitors including those specifically directed at CDK2. Delving into the results, we critically appraise the observed clinical efficacy and offer valuable insights into their potential impact and future applications. [Display omitted] •Preclinical efficacy of CDK2 blockade in MYC/CCNE1 overexpressed and CDK4/6i resistant cancer model.•Reigneted interest in selective targeting CDK2, with clinical devolpment of novel CDK inhibitors.•Favorable tolerability profile and significant antitumor activity of CDK2 inhibitors after CDK4/6i failure.•CDK4i and CDK2/4/6i, with or whitout ET, promising new drugs for refractory HR+ metastatic breast cancer.•Expected forthcoming data for novel CDKi best combinational strategies, population and setting.