A method for predicting the responsiveness of lymphomas to PI3K pathway inhibitors
Lymphomas are highly diverse and among the most common cancers in the US; approximately 1 in 50 Americans will be diagnosed with a lymphoma in their lifetime. Standard therapy for lymphomas generally includes chemotherapy, and while some cases are successfully treated, recurrence frequently occurs. Thus, researchers and clinicians are searching for alternative modalities to treat this widespread disease. The PI3K pathway is a desirable target for cancer therapy due to its well-characterized oncogenic function in a large variety of cancers, including lymphomas. However, to date, the therapeutic implication of targeting the PI3K pathway in lymphomas has not been fully explored.
Dr. Sandeep Dave and colleagues have recently studied the effectiveness of PI3K pathway inhibitors against 60 lymphoma cell lines, spanning multiple lymphoma subtypes, and demonstrated that PI3K pathway inhibition could effectively inhibit the growth of a broad range of lymphoma subtypes. Interestingly, their studies identified drug-sensitive and drug-resistant lymphoma lines within a shared histological classification, indicating that distinct lymphoma subtypes exhibit molecular heterogeneity that affects treatment outcome. Upon molecular characterization of the drug-resistant variants, Dr. Dave et al. discovered that PAK1 expression was associated with resistance to PI3K pathway inhibition. Additionally, pharmacological inhibition of PAK1 synergistically potentiated the effects of PI3K pathway inhibitors against drug-resistant lymphomas. This study suggests that PI3K pathway inhibitors may have utility for the treatment of a diverse array of lymphomas. Furthermore, PAK1 may serve as a viable biomarker and therapeutic target for predicting and augmenting the effectiveness of PI3K inhibitors for lymphomas, respectively.
Due to the relatively conserved nature of protein function across cell types, PAK1 may also contribute to PI3K inhibitor resistance in non-lymphoma tumors. Thus, the application of this technology may extend beyond lymphomas.
The current invention describes a molecular biomarker, PAK1, that may portend the therapeutic outcome of PI3K inhibitors for lymphomas. Additionally, this work suggests that PAK1 inhibition can synergistically enhance the effectiveness of PI3K pathway inhibitors.