Venetoclax Synergizes Sunitinib in Renal Cell Carcincoma through Inhibition of Bcl-2

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Abstract

Aims:

More effective treatment options for patients with renal cell carcinoma (RCC) are needed, in particular advanced RCC.

Background:

Sunitinib, a multitarget tyrosine kinase inhibitor, is a first-line treatment of metastatic RCC. However, the management of sunitinib-induced adverse events and resistance is complex. In hematological malignancies, effective targeting of anti-apoptotic proteins such as Bcl-2 has been achieved, but limited progress has been made in solid tumors.

Objective:

This work systematically investigated the therapeutic potential of the combination of sunitinib and venetoclax, a Bcl-2 inhibitor, in preclinical RCC models.

Methods:

Quantitative analysis of drug interactions was performed. Cell viability was examined after drug treatment or Bcl-2 siRNA depletion. RCC xenograft mouse model was applied to validate the efficacy of sunitinib and venetoclax.

Results:

A strong synergistic interaction between sunitinib and venetoclax was observed across a range of different dose levels in all tested RCC cell lines. Sequential treatment studies show that the sequential addition of venetoclax and then sunitinib is superior to concurrent treatment and the sequential addition of sunitinib and then venetoclax in decreasing RCC cell viability. The sensitivity of RCC cell lines to venetoclax treatment negatively correlates with their Bcl-2 levels. Specific depletion of Bcl-2 mimics the synergistic effects of venetoclax with sunitinib. Treatment of mice implanted with high Bcl-2-expressing RCC cells reveals that a combination of venetoclax and sunitinib at a non-toxic dose displays complete regression of tumor growth throughout the whole duration of treatment.

Conclusion:

Our work demonstrates that inhibiting Bcl-2 by venetoclax synergistically enhances sunitinib’s efficacy in RCC. Venetoclax holds great potential as a viable option for clinical use.

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Searching for Drug Synergy in Complex Dose–Response Landscapes Using an Interaction Potency Model

Bhagwan Yadav, Krister Wennerberg, Tero Aittokallio … (2015)

Rational design of multi-targeted drug combinations is a promising strategy to tackle the drug resistance problem for many complex disorders. A drug combination is usually classified as synergistic or antagonistic, depending on the deviation of the observed combination response from the expected effect calculated based on a reference model of non-interaction. The existing reference models were proposed originally for low-throughput drug combination experiments, which make the model assumptions often incompatible with the complex drug interaction patterns across various dose pairs that are typically observed in large-scale dose–response matrix experiments. To address these limitations, we proposed a novel reference model, named zero interaction potency (ZIP), which captures the drug interaction relationships by comparing the change in the potency of the dose–response curves between individual drugs and their combinations. We utilized a delta score to quantify the deviation from the expectation of zero interaction, and proved that a delta score value of zero implies both probabilistic independence and dose additivity. Using data from a large-scale anticancer drug combination experiment, we demonstrated empirically how the ZIP scoring approach captures the experimentally confirmed drug synergy while keeping the false positive rate at a low level. Further, rather than relying on a single parameter to assess drug interaction, we proposed the use of an interaction landscape over the full dose–response matrix to identify and quantify synergistic and antagonistic dose regions. The interaction landscape offers an increased power to differentiate between various classes of drug combinations, and may therefore provide an improved means for understanding their mechanisms of action toward clinical translation.

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BCL-2 family antagonists for cancer therapy.

Guillaume Lessene, Peter Czabotar, Peter M Colman (2008)

Overexpression of members of the BCL-2 family of pro-survival proteins is commonly associated with unfavourable pathogenesis in cancer. The convergence of cytotoxic stress signals on the extended BCL-2 protein family provides the biological rationale for directly targeting this family to induce apoptotic cell death. Recently, several compounds have been described that inhibit the interaction between BCL-2 family members and their natural ligand, a helical peptide sequence known as the BH3 domain. Here, we review preclinical and clinical data on these compounds, and recommend four criteria that define antagonists of the BCL-2 protein family.