SF3B1 Mutations Are Associated with Resistance to Non-Genotoxic MDM2 Inhibition in Chronic Lymphocytic Leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is a genetically and clinically heterogeneous malignancy affecting older individuals. There are a number of current treatment options for CLL, including monoclonal antibodies, targeted drugs, chemotherapy, and different combinations of these. However, for those patients who are intrinsically treatment resistant, or relapse following initial responses, novel targeted therapies are still needed. Targeting the mouse double-minute-2 human homolog (MDM2), a primary negative regulator of p53, is an appealing therapeutic strategy for non-genotoxic reactivation of p53, since the TP53 gene is in its wild-type state at diagnosis in approximately 90% of patients. Mutated SF3B1 and TP53 are both associated with more aggressive disease, resistance to therapies and poorer overall survival for CLL. In this study, we performed a screen for SF3B1 and TP53 mutations and tested RG7388 (idasanutlin), a second-generation MDM2 inhibitor, in a cohort of CLL primary patient samples. SF3B1 mutations were detected in 24 of 195 cases (12.3%) and found associated with poor overall survival (hazard ratio [HR] 2.12, p = 0.032) and high CD38 expression (median CD38 (%) 32 vs. 5; p = 0.0087). The novel striking finding of this study was an independent link between SF3B1 mutational status and poor response to RG7388. Overall, SF3B1 mutations in CLL patient samples were associated with resistance to treatment with RG7388 ex vivo, and patients with the wild type for both SF3B1 and TP53 are more likely to benefit from treatment with MDM2 inhibitors.

BCL2 Protein Progressively Declines during Robust CLL Clonal Expansion: Potential Impact on Venetoclax Clinical Efficacy and Insights on Mechanism

“…Thus, the clone might be expected to exhibit restrained growth but elevated survival unless the CD5+ clone acquires additional genetic aberrations to counteract the compromised growth/survival, which follows the significant stabilization of p53 protein during vigorous cell growth. While speculative, the above hypothesis is consistent with the typically slow progression of monoclonal B cell lymphocytosis (MBL) [122,123]; high prevalence of del(13q) in early MBL [124,125]; the better clinical outcome of CLL with del(13q) as the sole chromosomal anomaly [126]; and the progressive appearance of genetic anomalies that alter expression and/or function of p53, either directly (e.g., TP53, ATM, or MDM2) or indirectly (e.g., NOTCH1, SF3B1, BIRC3, and RPS15 [114,125,[127][128][129][130][131][132][133][134][135][136].…”

RNA Sequencing Reveals Candidate Genes and Pathways Associated with Resistance to MDM2 Antagonist Idasanutlin in TP53 Wild-Type Chronic Lymphocytic Leukemia

“…The TP53 and SF3B1 gene statuses were previously found to be statistically significant independent predictive variables for the response of CLL patient samples to RG7388 [2,4]. The TP53 status specifically distinguishes a subgroup of intermediate responders (1 µM < LC 50 < 10 µM) and resistant responders (LC 50 ≥ 10 µM) from the sensitive subgroup (LC 50 ≤ 1 µM).…”

“…However, the resistance mechanism in some TP53 wild-type subpopulations that are expected to respond to RG7388 is still not fully explained. The SF3B1 mutational status is an another important predicter in CLL [4], but other response biomarkers need to be investigated in CLL cells that have neither TP53 nor SF3B1 mutations but are still resistant. We, therefore, planned an RNA-seq study for a large-scale transcriptome analysis.…”

“…However, the CLL cell response to MDM2 inhibitors varies considerably, and although dependent on the TP53 mutational status, it also shows variation across TP53 WT samples. SF3B1 mutations in CLL patient samples were found to be associated with resistance to treatment with RG7388 ex vivo, and patients with the wild type for both SF3B1 and TP53 are most likely to benefit from treatment with MDM2 inhibitors [4]. To further explore the mechanisms involved in the differences in drug responses, RNA-seq analysis was carried out on a selection of TP53 WT primary CLL samples either resistant or sensitive to the MDM2 inhibitor RG7388, to define differentially expressed genes and pathways activated by RG7388 compared to untreated controls.…”

Advance in Targeted Cancer Therapy and Mechanisms of Resistance

“…Therefore, recent research has attempted to maximize the beneficial efficiency of targeted therapies by identifying patients with suitable biomarkers. Mutations in SF3B1 (subunit 1 of the splicing factor 3b protein complex) were found to be positively associated with poorer response to RG7388-based MDM2-targeted therapy in patients with chronic lymphocytic leukemia [4]. The serpin protein SPINK2 has been suggested as a potent adverse prognostic marker in acute myeloid leukemia, particularly in patients with NPM1 mutations [5].…”