Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, and therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways to overcome resistance, an urgent clinical need in all relapsed/refractory cancers, remains difficult. Through genomic analyses of clinical specimens, we show that metabolic reprogramming toward oxidative phosphorylation (OXPHOS) and glutaminolysis is associated with therapeutic resistance to the Bruton’s tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma (MCL), a B cell lymphoma subtype with poor clinical outcomes. Inhibition of OXPHOS with a clinically applicable small molecule, IACS-010759, which targets complex I of the mitochondrial electron transport chain, results in marked growth inhibition in vitro and in vivo in ibrutinib-resistant patient-derived cancer models. This work suggests that targeting metabolic pathways to subvert therapeutic resistance is a clinically viable approach to treat highly refractory malignancies.

Mantle cell lymphoma is an aggressive subtype of non-Hodgkin B cell lymphoma that is characterized by a poor prognosis determined by Ki67 and Mantle Cell International Prognostic Index scores, but it is becoming increasingly treatable. The majority of patients, especially if young, achieve a progression-free survival of at least 5 years. Mantle cell lymphoma can initially be treated with an anti-CD20 antibody in combination with a chemotherapy backbone, such as VR-CAP (the anti-CD20 monoclonal antibody rituximab administered with cyclophosphamide, doxorubicin, and prednisone) or R-CHOP (the anti-CD20 monoclonal antibody rituximab administered with cyclophosphamide, doxorubicin, vincristine, and prednisone). While initial treatment can facilitate recovery and complete remission in a few patients, many patients experience relapsed or refractory mantle cell lymphoma within 2 to 3 years after initial treatment. Targeted agents such as ibrutinib, an inhibitor of Bruton’s tyrosine kinase, which has been approved only in the relapsed setting, can be used to treat patients with relapsed or refractory mantle cell lymphoma. However, mantle cell lymphoma cells often acquire resistance to such targeted agents and continue to survive by activating alternate signaling pathways such as the PI3K-Akt pathway or the NF-κB pathways.NF-κB is a transcription factor family that regulates the growth and survival of B cells; mantle cell lymphoma cells depend on NF-κB signaling for continued growth and proliferation. The NF-κB signaling pathways are categorized into canonical and non-canonical types, wherein the canonical pathway prompts inflammatory responses, immune regulation, and cell proliferation, while the non-canonical leads to B cell maturation and lymphoid organogenesis. Since these pathways upregulate survival genes and tumor-promoting cytokines, they can be activated to overcome the inhibitory effects of targeted agents, thereby having profound effects on tumorigenesis. The NF-κB pathways are also highly targetable in that they are interconnected with numerous other pathways, including B cell receptor signaling, PI3K/Akt/mTOR signaling, and toll-like receptor signaling pathways. Additionally, elements of the non-canonical NF- κB pathway, such as NF-κB-inducing kinase, can be targeted to overcome resistance to targeting of the canonical NF- κB pathway.Targeting the molecular mechanisms of the NF-κB pathways can facilitate the development of novel agents to treat malignancies and overcome drug resistance in patients with relapsed or refractory mantle cell lymphoma.

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Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma that is largely chemoresistant. Ibrutinib, a drug that inhibits Bruton’s tyrosine kinase (BTK), has improved the overall survival of patients with MCL; however, resistance to ibrutinib has emerged as a decisive, negative factor in the prognosis of MCL. Adopting a more patient-centric therapeutic approach that incorporates applied genomics and interrogation of B cell signaling pathways may offer an alternative route to reach durable remission in patients with MCL. Although targeting genetic variants in MCL is not yet feasible in the clinical setting, the identification and targeting of increasingly active B cell signaling pathways may be a viable therapeutic strategy that may improve patient outcomes. Genome-editing tools and sequencing platforms could play dominant roles in patient-centric approaches of treatment in the future, potentially improving clinical outcomes for patients with MCL.

Background: Mantle cell lymphoma (MCL) accounts for 6% of all non-Hodgkin lymphoma and is a therapeutic challenge. Phosphoinositide-3 kinase (PI3K) has been shown to be an alternative survival pathway in relapsed/refractory MCL. KA2237 (designed by Karus Therapeutics Ltd, Oxfordshire, United Kingdom) is a dual inhibitor of the class I beta and delta isoforms of the 110 kDa catalytic subunit of PI3K. By selectively targeting PI3K-beta and -delta isoforms and preventing their activation, KA2237 may decrease proliferation and induce cell death in susceptible tumor cells. Methods: We assessed the effects of KA2237 on the in vitro cell proliferation of both ibrutinib-sensitive (Mino, Jeko-1, and Rec-1) and primary ibrutinib-resistant (Z-138 and Maver-1) cell lines, and acquired ibrutinib-resistant MCL cell line, Jeko-R. We also tested the viability of patient-derived xenograft (PDX) tumor cells to KA2237. We compared the efficacy of KA2237 with two other commercial PI3K inhibitors, duvelisib (IPI-145, Selleck) and idelalisib (Cal-101, Selleck). Also, we paired these three inhibitors (KA2237, duvelisib and idelalisib) each with ibrutinib to evaluate the potential synergistic effects of these combinations. Lastly, we also tested in vivo efficacy of KA2237 and its combination with ibrutinib in PDX tumor cells. Results: KA2237 inhibited cell proliferation in both ibrutinib-sensitive and ibrutinib-resistant cell lines in a dose-dependent and time-dependent manner. For Mino and Jeko-1, the IC50 was 4.8 uM and 2.9 uM and for Z-138 and Maver-1 cell lines, the IC50 was 0.6 uM and 0.1 uM, respectively. KA2237 also decreased cell viability of ibrutinib-sensitive and ibrutinib-resistant MCL PDX tumor cells. However, KA2237 did not decrease the cell viability of normal human peripheral blood mono-nuclear cells. KA2237 arrested phase G0/G1 in Rec-1 and Jeko-R cell lines. We detected the expression of PI3K isoforms in MCL, finding higher expression of PI3K β and δ in MCL-resistant cell lines as compared with sensitive cell lines. We found that KA2237 induced MCL cell apoptosis in a time-dependent and dose-dependent manner. In comparison with duvelisib and idelalisib, KA2237 achieved greater inhibition of cell viability, cell apoptosis and cell cycle arrest. Furthermore, we found synergistic effects of KA2237 and ibrutinib combination in several MCL cell lines and in PDX models. In an ibrutinib-resistant PDX model, KA2237 treated mice reduced tumor burden significantly compared with vehicle control, and higher tumor growth inhibition was achieved as compared with ibrutinib. Conclusion: The novel PI3K inhibitor, KA2237 may be a potential candidate for MCL therapy, especially in the ibrutinib-resistant cases. Disclosures Wang: Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding; BeiGene: Research Funding; Asana BioSciences: Research Funding; Kite Pharma: Research Funding; Celgene: Research Funding.