NP-ALT, a Liposomal:Peptide Drug, Blocks p27Kip1 Phosphorylation to Induce Oxidative Stress, Necroptosis, and Regression in Therapy-Resistant Breast Cancer Cells.

Abstract

Resistance to cyclin D-CDK4/6 inhibitors (CDK4/6i) represents an unmet clinical need and is frequently caused by compensatory CDK2 activity. Here we describe a novel strategy to prevent CDK4i resistance by using a therapeutic liposomal:peptide formulation, NP-ALT, to inhibit the tyrosine phosphorylation of p27Kip1(CDKN1B), which in turn inhibits both CDK4/6 and CDK2. We find that NP-ALT blocks proliferation in HR+ breast cancer cells, as well as CDK4i-resistant cell types, including triple negative breast cancer (TNBC). The peptide ALT is not as stable in primary mammary epithelium, suggesting that NP-ALT has little effect in nontumor tissues. In HR+ breast cancer cells specifically, NP-ALT treatment induces ROS and RIPK1-dependent necroptosis. Estrogen signaling and ERα appear required. Significantly, NP-ALT induces necroptosis in MCF7 ESRY537S cells, which contain an ER gain of function mutation frequently detected in metastatic patients, which renders them resistant to endocrine therapy. Here we show that NP-ALT causes necroptosis and tumor regression in treatment naïve, palbociclib-resistant, and endocrine-resistant BC cells and xenograft models, demonstrating that p27 is a viable therapeutic target to combat drug resistance. IMPLICATIONS: This study reveals that blocking p27 tyrosine phosphorylation inhibits CDK4 and CDK2 activity and induces ROS-dependent necroptosis, suggesting a novel therapeutic option for endocrine and CDK4 inhibitor-resistant HR+ tumors.

• Authors: Irina Jilishitz, Jason Luis Quiñones, Priyank Patel, Grace Chen, Jared Pasetsky, Allison VanInwegen, Scott Schoninger, Manasi P Jogalekar, Vladislav Tsiperson, Lingyue Yan, Yun Wu, Susan R S Gottesman, Jonathan Somma, Stacy W Blain
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 19 Issue 11 Pg. 1929-1945 (11 2021) ISSN: 1557-3125 [Electronic] United States
• PMID: 34446542 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Cdkn1b protein, mouse
• Protein Kinase Inhibitors
• Cyclin-Dependent Kinase Inhibitor p27

Topics

• Animals
• Breast Neoplasms (drug therapy, genetics, pathology)
• Cyclin-Dependent Kinase Inhibitor p27 (drug effects)
• Disease Models, Animal
• Female
• Humans
• Mice
• Mice, Inbred NOD
• Necroptosis (genetics)
• Oxidative Stress
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology, therapeutic use)