The development of drug resistance is a major challenge in cancer therapy. Mantle cell lymphoma (MCL), like many other human cancers, remains incurable mainly due to acquired drug resistance. Ibrutinib received approval from the U.S. Food and Drug Administration (FDA) for treatment of MCL in November 2013, and has shown promise in treating many MCL patients. Unfortunately, about one-third of patients are resistant to ibrutinib and many patients become resistant after the initial response. The tumors grow faster than before and there are no effective therapeutic options. The underlying mechanism is unknown. By longitudinal genomic and RNA sequencing analysis of both MCL tumors and healthy tissue we have identified a relapse-specific genetic mutation, C481S, in Burton’s Tyrosine Kinase (BTK), which ibrutinib specifically targets. This is the first identified mutation specific to MCL patients who relapse from ibrutinib after a durable response. However, this BTK mutation is not found in MCL patients who do not respond to ibrutinib or become resistance after transient response, suggesting two patterns of ibrutnib resistance.in MCL.
Ibrutinib resistance appears to correlate to an increased activation of a number of other molecular mechanisms known to contribute to lymphoma growth, among them the protein CDK4, and signaling along the PI3K-AKT pathway. We further discovered that targeting CDK4 with palbociclib (PD 0332991), a selective CDK4-inhibitor, made the MCL tumor cells sensitive to inhibitors of PI3K regardless of BTK mutation. These findings suggest that a combination therapy of palbociclib and PI3K inhibitor may overcome ibrutinib resistance. To address this exciting possibility, we will 1) investigate the mechanism by which inhibition of CDK4 sensitizes lymphoma cells to PI3K inhibitor, focusing on the disruption of glucose metabolism based on preliminary evidence; and 2) determine the clinical efficacy of overriding ibrutinib resistance by dual targeting of CDK4 and PI3K in a Phase I clinical trial in MCL, and discover genes and pathways that discriminate sensitivity and resistance by integrative longitudinal genomic and RNA sequencing analysis of serial biopsies before, during and after therapy.
This novel study not only suggests new approaches for treating MCL but also has implications for treatment of other B cell lymphomas, such as chronic lymphocytic leukemia and a diverse group of non-Hodgkin lymphomas. It is also exciting because CDK4 is a new kind of drug target; it controls the cell cycle, which is a central cancer pathway. As such, targeting CDK4 is not just important for MCL but for many forms of cancer. For example, when combined with letrozole, palbociclib more than doubled the progression free survival of metastatic breast cancer patients. Since PI3K is commonly mutated or over-activated in human cancers, including breast cancer, the palbociclib and PI3K combination represents a novel therapy for other human cancers as well.