Counteracting oxidative phosphorylation-mediated resistance of melanomas to MAPK pathway inhibition

AbstractTyrosine kinase inhibitors (TKIs) targeting FLT3 have shown activity but when used alone have achieved limited success in clinical trials, suggesting the need for combination with other drugs. We investigated the combination of FLT3 TKIs (Gilteritinib or Sorafenib), with Venetoclax, a BCL-2 selective inhibitor (BCL-2i), on FLT3/ITD leukemia cells. The combination of a FLT3 TKI and a BCL-2i synergistically reduced cell proliferation and enhanced apoptosis/cell death in FLT3/ITD cell lines and primary AML samples. Venetoclax also re-sensitized FLT3 TKI-resistant cells to Gilteritinib or Sorafenib treatment, mediated through MAPK pathway inhibition. Gilteritinib treatment alone dissociated BIM from MCL-1 but increased the binding of BIM to BCL-2. Venetoclax treatment enhanced the binding of BIM to MCL-1 but dissociated BIM from BCL-2. Treatment with the drugs together resulted in dissociation of BIM from both BCL-2 and MCL-1, with an increased binding of BIM to the cell death mediator BAX, leading to increased apoptosis. These findings suggest that Venetoclax mitigates the unintended pro-survival effects of FLT3 TKI mainly through the dissociation of BIM and BCL-2 and also decreased BIM expression. This study provides evidence that the addition of BCL-2i enhances the effect of FLT3 TKI therapy in FLT3/ITD AML treatment.

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B15 COP1 E3 Ligase Modulates Response to Oncogenic MAPK Pathway Inhibition

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2019.12.083 ◽

2020 ◽

Vol 15 (2) ◽

pp. S32

Author(s):

M.K. Mayekar ◽

L. Lin ◽

T.G. Bivona

Keyword(s):

Mapk Pathway ◽

E3 Ligase ◽

Pathway Inhibition

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Preclinical activity of cobimetinib alone or in combination with chemotherapy and targeted therapies in renal cell carcinoma

Future Oncology ◽

10.2217/fon-2021-0256 ◽

2021 ◽

Author(s):

Lichen Zhang ◽

Deqiong Xie ◽

Yonghua Lei ◽

Aoli Na ◽

Lei Zhu

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Mapk Pathway ◽

Standard Of Care ◽

Underlying Mechanism ◽

Mek Inhibitor ◽

Tumor Formation ◽

Pathway Inhibition ◽

New Treatments

Background: The poor outcome of advanced renal cell carcinoma (RCC) necessitates new treatments. Cobimetinib is a MEK inhibitor and approved for the treatment of melanoma. This work investigated the efficacy of cobimetinib alone and in combination with anti-RCC drugs. Methods: Proliferation and apoptosis assays were performed, and combination index was analyzed on RCC cell lines (CaKi-2, 786-O, A-704, ACHN and A489) and xenograft models. Immunoblotting analysis was conducted to investigate the MAPK pathway. Results: Cobimetinib was active against RCC cells, with IC50 at 0.006–0.8μM, and acted synergistically with standard-of-care therapy. Cobimetinib at nontoxic doses prevented tumor formation, inhibited tumor growth and enhanced efficacy of 5-fluorouracil, sorafenib and sunitinib via suppressing Raf/MEK/ERK, leading to MAPK pathway inhibition. Conclusion: Our findings demonstrate the potent anti-RCC activity of cobimetinib and its synergism with RCC standard-of-care drugs, and confirm the underlying mechanism of the action of cobimetinib.

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