Title:Venetoclax Synergizes Sunitinib in Renal Cell Carcincoma through Inhibition of
Bcl-2
Volume: 23
Issue: 18
Author(s): Yuanjia Tang, Tao Song, Liangkui Gao*Fei Mao*
Affiliation:
- Department of Urology, Xiangyang No.1 People’s Hospital, Hubei University of Medicine, Xiangyang, Hubei, People’s Republic of
China
- Department of Urology, Xiangyang No.1 People’s Hospital, Hubei University of Medicine, Xiangyang, Hubei, People’s Republic of
China
Keywords:
Venetoclax, sunitinib, Bcl-2, advanced RCC, synergism, renal cell carcinoma.
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.
