title: The role of PIM1 in the ibrutinib-resistant ABC subtype of diffuse large B-cell lymphoma.
abstract: Diffuse large B cell lymphoma (DLBCL) is a heterogeneous lymphoma and the most common subtype of non-Hodgkin lymphoma, accounting for roughly 30% of newly diagnosed cases in the United States. DLBCL can be separated into the activated B cell-like (ABC) and germinal center B cell-like (GCB) subtypes, with distinct gene expression profiles, oncogenic aberrations, and clinical outcomes. ABC-DLBCL is characterized by chronically active B-cell receptor (BCR) signaling that can be modulated by Bruton's tyrosine kinase (BTK) activity. Thus, BTK serves as an attractive therapeutic target in this type of B-cell malignancy. Ibrutinib, a first-in-class, orally available covalent BTK inhibitor, has demonstrated clinical activity in several B-cell leukemias and lymphomas. A phase 1/2 clinical trial of single-agent ibrutinib in relapsed and refractory DLBCL patients revealed an overall response rate of 37% in ABC-DLBCL patients. However, responses to kinase-directed therapies are often limited by emerging resistance mechanisms that bypass the therapeutic target. Here we report the discovery of point mutations within the kinase PIM1 that reduce sensitivity to ibrutinib in ABC-DLBCL. These mutations stabilize PIM1 and affect upstream regulators and downstream targets of NF-κB signaling. The introduction of mutant PIM1 into an ABC-DLBCL cell line, TMD8, increased colony formation and decreased sensitivity to ibrutinib. In addition, ibrutinib-resistant cell lines generated by prolonged ibrutinib exposurein vitroupregulated PIM1 expression, consistent with a role for PIM1 in antagonizing ibrutinib activity. The combination of a pan-PIM inhibitor with ibrutinib synergistically inhibited proliferationin vitroand tumor growthin vivo. Together, these data provide a rationale for combining BTK and PIM1 inhibition in the treatment of ABC-DLBCL.
authors.affiliation: Department of Research, Pharmacyclics, LLC, an AbbVie Company Sunnyvale, CA, USA.
authors.forename: Hsu-Ping
authors.initials: HP
authors.lastname: Kuo
authors.affiliation: Department of Research, Pharmacyclics, LLC, an AbbVie Company Sunnyvale, CA, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Ezell
authors.affiliation: Department of Research, Pharmacyclics, LLC, an AbbVie Company Sunnyvale, CA, USA.
authors.forename: Sidney
authors.initials: S
authors.lastname: Hsieh
authors.affiliation: Department of Research, Pharmacyclics, LLC, an AbbVie Company Sunnyvale, CA, USA.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Schweighofer
authors.affiliation: Department of Research, Pharmacyclics, LLC, an AbbVie Company Sunnyvale, CA, USA.
authors.forename: Leo Wk
authors.initials: LW
authors.lastname: Cheung
authors.affiliation: Department of Research, Pharmacyclics, LLC, an AbbVie Company Sunnyvale, CA, USA.
authors.forename: Shiquan
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Research, Pharmacyclics, LLC, an AbbVie Company Sunnyvale, CA, USA.
authors.forename: Mutiah
authors.initials: M
authors.lastname: Apatira
authors.affiliation: Department of Research, Pharmacyclics, LLC, an AbbVie Company Sunnyvale, CA, USA.
authors.forename: Mint
authors.initials: M
authors.lastname: Sirisawad
authors.affiliation: Department of Research, Pharmacyclics, LLC, an AbbVie Company Sunnyvale, CA, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Eckert
authors.affiliation: Department of Research, Pharmacyclics, LLC, an AbbVie Company Sunnyvale, CA, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Research, Pharmacyclics, LLC, an AbbVie Company Sunnyvale, CA, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Hsu
authors.affiliation: Department of Research, Pharmacyclics, LLC, an AbbVie Company Sunnyvale, CA, USA.
authors.forename: Chun-Te
authors.initials: CT
authors.lastname: Chen
authors.affiliation: Department of Research, Pharmacyclics, LLC, an AbbVie Company Sunnyvale, CA, USA.
authors.forename: Darrin
authors.initials: D
authors.lastname: Beaupre
authors.affiliation: Department of Research, Pharmacyclics, LLC, an AbbVie Company Sunnyvale, CA, USA.
authors.forename: Betty Y
authors.initials: BY
authors.lastname: Chang
keywords: Bruton’s tyrosine kinase; DLBCL; PIM1; ibrutinib