NP-ALT, a Liposomal:Peptide Drug, Blocks p27Kip1 Phosphorylation to Induce Oxidative Stress, Necroptosis, and
Irina Jilishitz1, Jason Luis Quiñones1, Priyank Patel2
1Department of Cell Biology and Pediatrics, SUNY Downstate Medical Center, Brooklyn, New York.
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.
Insights
A novel therapeutic, NP-ALT, targets p27 phosphorylation to inhibit CDK4/6 and CDK2 activity, overcoming resistance in breast cancer. This approach induces cell death and tumor regression, offering a new treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are effective against HR+ breast cancer but resistance is a significant clinical challenge.
- Compensatory CDK2 activity is a key mechanism driving resistance to CDK4/6 inhibitors.
- p27Kip1 (CDKN1B) is a critical regulator of cell cycle progression, and its phosphorylation status influences CDK activity.
Purpose of the Study:
- To develop a novel therapeutic strategy to overcome resistance to CDK4/6 inhibitors in breast cancer.
- To investigate the efficacy of NP-ALT, a liposomal:peptide formulation targeting p27Kip1 phosphorylation, in preclinical models of breast cancer.
- To explore the mechanisms of action of NP-ALT, including its effects on cell proliferation, cell death, and signaling pathways.
Main Methods:
- Utilized a liposomal:peptide formulation (NP-ALT) designed to inhibit p27Kip1 tyrosine phosphorylation.
- Assessed NP-ALT's effects on cell proliferation in various breast cancer cell lines, including hormone receptor-positive (HR+) and triple-negative breast cancer (TNBC) models.
- Investigated NP-ALT-induced cell death pathways, focusing on reactive oxygen species (ROS) and receptor-interacting protein kinase 1 (RIPK1)-dependent necroptosis.
- Evaluated NP-ALT efficacy in treatment-naïve, palbociclib-resistant, and endocrine-resistant breast cancer cell lines and xenograft models.
Main Results:
- NP-ALT effectively blocked proliferation in HR+ breast cancer cells and CDK4i-resistant cell types, including TNBC.
- NP-ALT demonstrated specificity for tumor tissues, with limited effects on normal mammary epithelium due to peptide stability.
- In HR+ breast cancer cells, NP-ALT induced ROS and RIPK1-dependent necroptosis, requiring estrogen signaling and ERα.
- NP-ALT induced necroptosis and tumor regression in various resistant breast cancer models, including those with ER gain-of-function mutations.
Conclusions:
- Blocking p27 tyrosine phosphorylation is a viable therapeutic strategy to combat CDK4/6 inhibitor resistance in breast cancer.
- NP-ALT inhibits both CDK4/6 and CDK2 activity by targeting p27Kip1, thereby overcoming resistance mechanisms.
- NP-ALT induces ROS-dependent necroptosis, presenting a novel therapeutic option for endocrine and CDK4 inhibitor-resistant HR+ breast tumors.
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