The PDPK1–RSK2 axis as a potential convergent therapeutic vulnerability in B-cell lymphomas

INTRODUCTION: B-cell lymphomas (BCLs) are the most prevalent group of hematologic cancers, encompassing various subtypes, each with a distinct clinical course shaped by cell of origin, genetics, and etiology. Recent advances in subtype-specific immunochemotherapy, targeted therapies, and cellular immunotherapy have improved outcomes for BCLs; nonetheless, some cases remain resistant to existing treatments. To address these resistant disease states, especially across multiple subtypes, the development of new universal targeted therapies could be transformative. AREAS COVERED: This review first highlights what distinguishes the PDPK1/RSK2 signaling axis, outlines its normal biological functions, and briefly examines its roles in solid tumors. It then narrows the focus to BCLs, supported by evidence from our research on pathway activation, functional dependence, prognostic value, and early-stage drug development. EXPERT OPINION: The PDPK1/RSK2 axis is activated in nearly all BCL subtypes and likely plays a significant role in disease development. This suggests the potential for treatments that work across subtypes, despite their genetic and phenotypic differences. Targeting a shared signaling pathway might help overcome resistance seen with traditional precision medicine and support the development of new therapies for rare disease subtypes. However, because current research remains preclinical, more work is necessary.