New Mechanism and Therapeutic Role of DNA Replication Licensing in Anti-CDK4/6 Resistance
Abstract
Background and Rationale: More than 70% of breast cancer patients are diagnosed with estrogen receptor-positive (ER+)/HER2-negative (-) breast cancer. These patients are treated with endocrine therapy, but endocrine resistance is common. In the last decade, one of the advances in treating ER+/HER2- breast cancer is the addition of CDK4/6 inhibitors (CDK4/6i) into endocrine therapy, which led to the recent FDA approval of using CDK4/6i (e.g., palbociclib) as a new standard of care. However, primary and secondary resistance to CDK4/6i emerges as an immense challenge. Patients treated with CDK4/6i often have to switch to chemotherapy within 6 months because of anti-CDK4/6 resistance. In addition, no clinical biomarkers are currently available to select patients who may or may not benefit from CDK4/6i. We now discover minichromosome maintenance 2 (MCM2) as a promising new biomarker and therapeutic target to treat ER+/HER2- BC resistant to CDK4/6i. MCM2 is a key component of the MCM complex required for DNA replication at an initial step called “origin licensing.” We find that high expression of the genes involved in origin licensing (MCM2 as the top one) is highly correlated to anti-CDK4/6 resistance in tumors from a recent clinical trial and in our relevant preclinical resistant cell models. Importantly, we observe that anti-CDK4/6-resistant cells are more vulnerable to MCM2 gene knockdown than the sensitive cells with low licensing gene expression. These findings have immediate clinical implications supporting the development of a new strategy targeting MCM2 as a therapeutic vulnerability and also a biomarker for anti-CDK4/6-resistant breast cancer. Objective and Aims: Our objective of this proposal is to elucidate a new mechanism of excess origin licensing in conferring resistance to CDK4/6i, and to provide a proof of principle targeting a therapeutic vulnerability and a biomarker of anti-CDK4/6 resistance. To achieve this goal, we propose the following three specific aims: Aim 1: To elucidate the molecular mechanism by which excess origin licensing activates CDK2 upon CDK4/6 inhibition. We will use our preclinical resistant cell models to determine the mechanism whereby excess origin licensing bypasses the anti-tumor effect of CDK4/6i, therefore conferring resistance. Aim 2: To determine whether excess origin licensing relieves replication stress induced by CDK4/6i. We will perform a series of assays to characterize and compare origin licensing and replication stress in response to CDK4/6i in resistant vs. sensitive cell models. Aim 3: To examine therapeutic potential of targeting MCM2 and clinical importance of origin licensing in anti-CDK4/6 resistance. We will perform a series of in vitro and in vivo experiments to assess anti-MCM2 in preferentially killing anti-CDK4/6-resistant BC cells with high licensing gene expression. We will also confirm the clinical importance of the licensing genes (MCM2 in particular) in predicting anti-CDK4/6 response by analyzing the RNA-seq data from a new neoadjuvant PALLET trial (NCT02296801). Overarching Challenges: Our proposed research will address two challenges: 1) “Identify what drives breast cancer growth and determine how to stop it” and 2) “Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival.” Who This Project Will Help: This study will primarily help > 25,000 women with ER+/HER2- breast cancer with intrinsic or acquired resistance to CDK4/6i, the standard of care, every year in the US. Potential Clinical Applications: The results of this study will support a new biomarker to predict response to CDK4/6i at diagnosis. This study will also support the development of new anti-MCM2 therapies that enable clinicians to treat patients, in advance, who may need additional and more effective treatment. Time to Patient-Related Outcomes: The results of this study will facilitate the development
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110610
Entities
People
- Xiaoyong Fu
Organizations
- Baylor College of Medicine
- United States Army