Drug resistance in cancer treatment, particularly in metastatic ER-positive breast cancer, poses a significant challenge. Dr. Sarat Chandarlapaty and his team have made strides in understanding why resistance to CDK4/6 inhibitors occurs. Their research, published in Cancer Cell, suggests that mutations in the p53 gene may play a crucial role in allowing tumor cells to overcome dormancy and resume growth, leading to resistance.
CDK4/6 inhibitors are designed to halt the growth cycle of tumor cells by promoting dormancy. However, resistance can develop when these cells escape dormancy. Dr. Chandarlapaty's hypothesis that p53 gene mutations are a key factor in this resistance was supported by their studies. They found that specific p53 mutations were present in patients with short-lived responses to CDK4/6 inhibitors. Additionally, changes in the RBL2 component of the DREAM complex, which is crucial for cell cycle regulation, were identified in p53-mutated tumor models.
The team's investigation into the assembly of the DREAM complex revealed that RBL2 was phosphorylated, a modification that could prevent the complex from assembling and thus allow tumor cells to resume growth. This led them to explore the role of CDK2 kinase, another cell cycle protein, in this process. They discovered that CDK2 activity could enable p53-mutated tumors to escape dormancy. By inhibiting both CDK2 and CDK4/6, they were able to induce a deep, irreversible growth-arrested state in p53-mutated tumors.
These findings underscore the importance of the p53 gene and the DREAM complex in the effectiveness of CDK4/6 inhibitors. They also suggest that highly selective CDK2 inhibitors could be a promising treatment for patients with p53-mutated tumors, potentially preventing resistance and metastasis in ER-positive breast cancer. Clinical trials for CDK2 inhibitors are currently underway at Dr. Chandarlapaty's institution, offering hope for more effective treatments in the future.
