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Venetoclax resistance: mechanistic insights and future strategies.

ABSTRACT: Acute myeloid leukemia (AML) is historically associated with poor prognosis, especially in older AML patients unfit for intensive chemotherapy. The development of Venetoclax, a potent oral BH3 (BCL-2 homology domain 3) mimetic, has transformed the AML treatment. However, the short duration of response and development of resistance remain major concerns. Understanding mechanisms of resistance is pivotal to devising new strategies and designing rational drug combination regimens. In this review, we will provide a comprehensive summary of the known mechanisms of resistance to Venetoclax and discuss Venetoclax-based combination therapies. Key contributing factors to Venetoclax resistance include dependencies on alternative anti-apoptotic BCL-2 family proteins and selection of the activating kinase mutations. Mutational landscape governing response to Venetoclax and strategic approaches developed considering current knowledge of mechanisms of resistance will be addressed.

SUBMITTER: Ong F

PROVIDER: S-EPMC9255248 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Venetoclax resistance: mechanistic insights and future strategies.

Ong Faustine F Kim Kunhwa K Konopleva Marina Y MY

Cancer drug resistance (Alhambra, Calif.) 20220506 2

Acute myeloid leukemia (AML) is historically associated with poor prognosis, especially in older AML patients unfit for intensive chemotherapy. The development of Venetoclax, a potent oral BH3 (BCL-2 homology domain 3) mimetic, has transformed the AML treatment. However, the short duration of response and development of resistance remain major concerns. Understanding mechanisms of resistance is pivotal to devising new strategies and designing rational drug combination regimens. In this review, w ...[more]

PMID: 35800373

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Project description:BackgroundVenetoclax (ABT-199), a first-in-class orally bioavailable BCL-2-selective inhibitor, was recently approved by the FDA for use in patients with 17p-deleted chronic lymphocytic leukemia who have received prior therapy. It is also being evaluated in numerous clinical trials for treating patients with various hematologic malignancies. As with any targeted cancer therapy, it is critically important to identify potential mechanisms of resistance, both for patient stratification and developing strategies to overcome resistance, either before it develops or as it emerges.MethodsIn order to gain a more comprehensive insight into the nature of venetoclax resistance mechanisms, we evaluated the changes in the BCL-2 family members at the genetic and expression levels in seven different venetoclax-resistant derived leukemia and lymphoma cell lines.ResultsGene and protein expression analyses identified a number of different alterations in the expression of pro- and anti-apoptotic BCL-2 family members. In the resistant derived cells, an increase in either or both the anti-apoptotic proteins BCL-XL or MCL-1, which are not targeted by venetoclax was observed, and either concomitant or exclusive with a decrease in one or more pro-apoptotic proteins. In addition, mutational analysis also revealed a mutation in the BH3 binding groove (F104L) that could potentially interfere with venetoclax-binding. Not all changes may be causally related to venetoclax resistance and may only be an epiphenomenon. For resistant cell lines showing elevations in BCL-XL or MCL-1, strong synergistic cell killing was observed when venetoclax was combined with either BCL-XL- or MCL-1-selective inhibitors, respectively. This highlights the importance of BCL-XL- and MCL-1 as causally contributing to venetoclax resistance.ConclusionsOverall our study identified numerous changes in multiple resistant lines; the changes were neither mutually exclusive nor universal across the cell lines tested, thus exemplifying the complexity and heterogeneity of potential resistance mechanisms. Identifying and evaluating their contribution has important implications for both patient selection and the rational development of strategies to overcome resistance.

Project description:Recent epidemiological studies have implicated chloride, rather than sodium, as the driver of poor survival previously attributed to hyponatremia in heart failure. Accumulating basic science evidence has identified chloride as a critical factor in renal salt sensing. Our goal was to probe the physiology bridging this basic and epidemiological literature. Two heart failure cohorts were included: (1) observational: patients receiving loop diuretics at the Yale Transitional Care Center (N=162) and (2) interventional pilot: stable outpatients receiving ≥80 mg furosemide equivalents were studied before and after 3 days of 115 mmol/d supplemental lysine chloride (N=10). At the Yale Transitional Care Center, 31.5% of patients had hypochloremia (chloride ≤96 mmol/L). Plasma renin concentration correlated with serum chloride (r=-0.46; P<0.001) with no incremental contribution from serum sodium (P=0.49). Hypochloremic versus nonhypochloremic patients exhibited renal wasting of chloride (P=0.04) and of chloride relative to sodium (P=0.01), despite better renal free water excretion (urine osmolality 343±101 mOsm/kg versus 475±136; P<0.001). Hypochloremia was associated with poor diuretic response (odds ratio, 7.3; 95% confidence interval, 3.3-16.1; P<0.001). In the interventional pilot, lysine chloride supplementation was associated with an increase in serum chloride levels of 2.2±2.3 mmol/L, and the majority of participants experienced findings such as hemoconcentration, weight loss, reduction in amino terminal, pro B-type natriuretic peptide, increased plasma renin activity, and increased blood urea nitrogen to creatinine ratio. Hypochloremia is associated with neurohormonal activation and diuretic resistance with chloride depletion as a candidate mechanism. Sodium-free chloride supplementation was associated with increases in serum chloride and changes in several cardiorenal parameters. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02031354.

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Venetoclax resistance: mechanistic insights and future strategies.

Publications

Venetoclax resistance: mechanistic insights and future strategies.

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