Pre-Clinical Evaluation of the PI3K-p110β/δ Inhibitor KA2237 in Mantle Cell Lymphoma

Abstract

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.

Regulation of B Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas

“…These inhibitors can be divided into non-selective pan inhibitors, targeting all isoforms, or isoform-specific inhibitors, which are more selective and have fewer off-target effects [98]. There are several pan inhibitors, of which we highlight buparlisib, with a subnanomolar activity against PI3Kα, β, γ, and δ [99]; copanlisib, a second-generation inhibitor against the α and δ isoforms [100,101]; KA2237, against the α and β isoforms and with tumorigenic properties in both sensitive-and ibrutinib-resistant cells in MCL cell lines and PDX tumors [102]; tenalisib (RP6530), a dual PI3K δ/γ inhibitor with an enhanced antitumor response by targeting both lymphoma cells and its microenvironment [103]. In addition, there are isoform-specific inhibitors for PI3Kα, such as, taselisib (GDC-0032) with a synergistic anti-proliferation activity in DLBCL cell lines when combined with venetoclax [104]; alpelisib, with a marginal response when used as a single agent [105] and BYL719, which combined with idelalisib cooperates and inhibitors the proliferation in ABC-DLBCL cell lines [106].…”

Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas

“…These inhibitors can be divided into non-selective pan inhibitors, targeting all isoforms, or isoform-specific inhibitors, which are more selective and have fewer off-target effects [ 97 ]. There are several pan inhibitors, of which we highlight buparlisib, with a subnanomolar activity against PI3Kα, β, γ, and δ [ 98 ]; copanlisib, a second-generation inhibitor against the α and δ isoforms [ 99 , 100 ]; KA2237, against the α and β isoforms and with tumorigenic properties in both sensitive- and ibrutinib-resistant cells in MCL cell lines and PDX tumors [ 101 ]; and tenalisib (RP6530), a dual PI3K δ/γ inhibitor with an enhanced antitumor response by targeting both lymphoma cells and its microenvironment [ 102 ]. In addition, there are isoform-specific inhibitors for PI3Kα, such as taselisib (GDC-0032) with a synergistic antiproliferation activity in DLBCL cell lines when combined with venetoclax [ 103 ]; alpelisib, with a marginal response when used as a single agent [ 104 ] and BYL719, which combined with idelalisib cooperates and inhibitors the proliferation in ABC-DLBCL cell lines [ 105 ].…”

Treatment Landscape of Relapsed/Refractory Mantle Cell Lymphoma: An Updated Review

“…Oral duvelisib (IPI-145) is another PI3K inhibitor studied in MCL mice models and showed a significant efficacy (62). The PI3K inhibitor KA2237 has also been demonstrated synergistic cytotoxicity in mice models with pre-clinical effectiveness in those with ibrutinib resistance (63). An assessment of the safety/tolerability of KA2237 in a phase-I open-label ascending dose trial (NCT02679196) is ongoing.…”