Abstract LB265: IpY.20: Innovative strategies for post-CDK estrogen receptor (ER)+ metastatic breast cancer (mBC)
Authors: Chen Grace , Dudas Natalie , Coleman Kate , Guido Carolina , Zisman Natalia , Allamneni Krishna , Blain Stacy Wister 
Published: April 2024

Cyclin-dependent kinases (CDK) 4/6 are key cell cycle regulators that form complexes with cyclin D1 and the master regulator p27Kip1. This ternary complex acts downstream of the ER- and HER2-pathways, which drive cell proliferation. CDK4/6 phosphorylates the Retinoblastoma protein and other substrates, and keeps p27 from inhibiting G1-associated CDK2. Targeted inhibition of CDK4/6 (CDK4/6i) blocks the growth of ER+ and HER2+ BC by dissolving the CDK4/6-cyclin D1 complex and permitting the shuttling of p27 to inhibit CDK2 complex. Approval of CDK 4/6i such as palbociclib, though a game changer for ER+ mBC, resulted in tumor resistance, leaving patients without effective treatments and a 5-yr survival of only 30%. Although CDK2 inhibitors (CDK2i) address compensatory CDK2 activity bypassing CDK4/6i, a key resistance mechanism, they lack selectivity due to CDK homology, resulting in off-target toxicity. To inhibit CDK2/4/6 simultaneously, combinations of CDK4/6i and CDK2i monotherapies were attempted, but the lack of coordination between CDK4/6 and CDK2 inhibition resulted in suboptimal efficacy. Concarlo presents a unique therapeutic rationale for directly targeting the CDK master regulator p27 to simultaneously inhibit CDK2/4/6 in a concerted manner, one that is guided by the role of p27 to turn all of the G1 CDKs ON and OFF during periods of proliferation and quiescence, respectively. This transition is facilitated by BRK (Breast tumor kinase)-mediated phosphorylation of p27. When p27 is Y phosphorylated, it converts CDK4/6 and CDK2 into open, active complexes. An endogenous BRK-spliced variant ALT can competitively bind to p27, block Y phosphorylation and lock CDK2/4/6 in the OFF conformation. Concarlo engineered a shorter variant of ALT (CCL20) and packaged in cationic liposomes for intracellular delivery, creating a novel IpY.20 drug product. As a single agent, IpY.20 inhibits cell proliferation in treatment-naïve and CDK4i-resistant HR+ cells with reduced non-tumor cell activity. In combination, IpY.20 enhances CDK4/6i responses in treatment-naïve HR+ cells, making it a potential front-line mBC therapy. While other CDKi activity is limited to cytostasis, IpY.20 shows dual cytostasis-cytotoxicity, potentially a more durable option. IpY.20 does not cause neutropenia commonly seen with other CDKis, and rescues the CDK4/6i-induced neutropenia in mice, suggesting better clinical tolerability. These findings underscore the significance of coordinated targeting of CDK2/4/6, making IpY.20 a first-in-class product uniquely exploiting p27-mediated CDK2/4/6 regulation. Direct targeting of p27 presents a new treatment paradigm bypassing the challenges of ATP-competitive CDKis, with potential to expand into tumor types with aberrant p27, CDK2/4/6 activity, or RAS/MAPK pathways that increase CDK4/6 activity.

Citation Format: Grace Chen, Natalie Dudas, Kate Coleman, Carolina Guido, Natalia Zisman, Krishna Allamneni, Stacy Wister Blain. IpY.20: Innovative strategies for post-CDK estrogen receptor (ER)+ metastatic breast cancer (mBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB265.