MS-553, a Selective PKC-ß Inhibitor Inhibits BCR Signaling and Synergizes with Venetoclax for the Treatment of High Risk CLL

Inhibitors of Bruton's tyrosine kinase (BTK) have been transformative in treating patients with chronic lymphocytic leukemia (CLL) due to their ability to inhibit B-Cell Receptor (BCR) signaling. However, despite durable remissions in many patients, complete responses are uncommon and acquired mutations in BTK and its downstream target phospholipase Cγ2 (PLCγ2) lead to relapses and poor survival. In parallel, genomic high-risk features such as aberrations in TP53 represent an independent risk factor that favor progression on BTK inhibitors (BTKi). TP53 aberrations comprise of deletions in chromosome 17 (del17p) which result in the loss of one allele of TP53 and point mutations in the TP53 gene. CLL patients with del17p acquire clonal mutations that affect the other p53 allele in 82% of cases and largely express only mutant TP53 protein. Therefore, there is an urgent need to identify therapies for patients who progress on BTKi.

We have observed over-expression of protein kinase C-β (PKC-β) in primary CLL patient samples including in those that have mutations in TP53. PKC-β is a downstream of the BCR and functions downstream of BTK. PKC-β is required for CLL cell survival and proliferation and therefore can be a potential target for patients with mutations in p53 that do not respond to other targeted therapies. We hypothesized that targeting PKC-β will inhibit BCR signaling downstream of BTK and may offer an effective therapeutic strategy for patients who relapse on ibrutinib. Mechanistically, we found that CLL cells (n=6 patients) in contact with stromal support upregulated their levels of PKC-β. Pre-exposure of stromal cells to MS-553, a selective PKC-β inhibitor prevented the stromal cell contact-induced increase in PKC-β within the CLL cells establishing that stromal contact was an important source of PKC-β in CLL cells.

We have shown in primary CLL patient samples that exposure to MS-553 decreases activation of PKC-β and its downstream effectors GSK3-β and ERK in a dose-dependent manner regardless of mutations in p53 both in the presence and absence of stromal support. In parallel, MS-553 also decreased the levels of BCL-xL, a key pro-survival BCL2 family protein via downregulation of β-catenin. Using dynamic BH3 profiling we show that CLL samples (both WT and mutant TP53) exposed to MS-553 (5µM, 24h) increase their dependence on BCL-2 and BCL-xL for survival. This finding suggested that MS-553 could synergize with the BCL-2 inhibitor venetoclax to eliminate CLL cells. Correspondingly, cells exposed to a combination of MS-553 and venetoclax released more cytochrome c (Cyt c), used as a measure of mitochondrial dysfunction, compared to each single agent alone and led to a synergistic increase in apoptosis as measured by Annexin V positivity.

These data provide strong rationale for an ongoing Phase I/II trial that evaluates MS-553 as a single agent and in combination with targeted agents such as venetoclax. Early interim data indicate that MS-553 is safe, tolerable and effective both as a single agent and in combination with venetoclax.

Jain:CareDx: Honoraria; Medisix: Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; Ipsen: Honoraria; Mingsight: Research Funding; Loxo Oncology: Research Funding; Takeda: Research Funding; MEI Pharma: Honoraria; TG Therapeutics: Honoraria; Cellectis: Honoraria, Research Funding; Beigene: Honoraria; TransThera Sciences: Research Funding; Newave: Research Funding; Novalgen: Research Funding; Dialectic Therapeutics: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Incyte Corporation: Research Funding; Pfizer: Research Funding; Cellectis: Honoraria, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support; Pharmacyclics, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Servier Pharmaceuticals LLC: Research Funding; ADC Therapeutics: Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding. Wierda:Oncternal Therapeutics, Inc.: Research Funding; Janssen: Research Funding; GSK/Novartis: Research Funding; Miragen: Research Funding; Juno: Research Funding; Sanofi: Consultancy; Gilead Sciences: Research Funding; Genentech: Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; Pharmacyclics LLC: Research Funding; Bristol Meyers Squibb (Juno and Celgene): Research Funding; Kite, a Gilead Company: Research Funding; Karyopharm: Research Funding; Genzyme: Consultancy; Xencor: Research Funding; Sunesis: Research Funding; AbbVie: Research Funding; AstraZeneca/Acerta Pharma. Inc.: Research Funding; Cyclacel: Research Funding. Zhang:MingSight Pharmaceuticals: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Niesman:MingSight Pharmaceuticals: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Woyach:Janssen: Consultancy; Genentech: Consultancy; AstraZeneca: Consultancy; Newave: Consultancy; Schrodinger: Research Funding; MorphoSys: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy; ArQule: Consultancy; Loxo@Lilly: Research Funding; Pharmacyclics: Consultancy. Sampath:Newwave: Honoraria.