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Published on: April 26, 2024
GZ17-6.02 and axitinib interact to kill renal carcinoma cells
Laurence Booth1, Cameron West2, Robert P Moore2
1Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Abstract:
GZ17-6.02 is undergoing clinical evaluation in solid tumors and lymphoma. The present studies were performed to define its biology in renal carcinoma cells and to determine whether it interacted with axitinib to enhance tumor cell killing. GZ17-6.02 interacted in an arithmetically greater than additive fashion with axitinib to kill kidney cancer cells. GZ17-6.02 and axitinib cooperated to inactivate ERBB2, c-MET, c-KIT, c-SRC, the AMPK, STAT3, STAT5 and eIF2α and to activate PERK, ULK1 and ATG13. The drugs interacted to increase the expression of FAS-L and to decrease the levels of MCL1, BCL-XL, and HDACs 1-3. The drugs as single agents inactivated the Hippo pathway. GZ17-6.02 and axitinib interacted to enhance autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5, eIF2α, toxic BH3 domain proteins or CD95/FADD significantly reduced drug combination lethality. GZ17-6.02 and axitinib increased the expression of BAK, BIM, Beclin1 and ATG5, effects blocked by knock down of eIF2α. The drugs increased phosphorylation of ULK1 S757 and ATG13 S318 and decreased the phosphorylation of mTORC1 and mTORC2, effects blocked by knock down of AMPKα. Knock down of Beclin1 or ATG5 prevented the drug combination reducing expression of HDACs 1-3 and from enhancing the expression of MHCA. Knock down of HDACs 1-3 enhanced MHCA expression. We conclude that GZ17-6.02 and axitinib interact to kill requiring ER stress signaling, autophagy and death receptor signaling. Autophagic degradation of HDACs played a key role in enhancing MHCA expression and of a potential improved response to checkpoint inhibitory immunotherapy.
Insights
GZ17-6.02 and axitinib synergistically kill kidney cancer cells by activating ER stress and autophagy, leading to enhanced cell death signaling. This combination therapy shows promise for improving immunotherapy responses.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- GZ17-6.02 is under clinical investigation for solid tumors and lymphoma.
- Renal cell carcinoma (RCC) presents a need for novel therapeutic strategies.
- Understanding drug interactions is crucial for optimizing cancer treatment.
Purpose of the Study:
- To elucidate the biological mechanisms of GZ17-6.02 in renal carcinoma cells.
- To determine the synergistic potential of GZ17-6.02 in combination with axitinib for enhanced tumor cell killing.
- To investigate the molecular pathways modulated by the drug combination.
Main Methods:
- In vitro studies using renal carcinoma cell lines.
- Assessment of cell viability and apoptosis.
- Analysis of key signaling pathways including ER stress, autophagy, and death receptor pathways.
- Gene knockdown experiments to identify essential mediators of drug efficacy.
Main Results:
- GZ17-6.02 and axitinib demonstrated supra-additive cytotoxicity in kidney cancer cells.
- The combination inactivated key signaling molecules (e.g., ERBB2, c-MET, AMPK, STAT3) and activated others (e.g., PERK, ULK1).
- Enhanced autophagosome formation, autophagic flux, and increased expression of pro-apoptotic proteins (BAK, BIM) were observed.
- The combination increased FAS-L and decreased survival proteins (MCL1, BCL-XL, HDACs).
Conclusions:
- GZ17-6.02 and axitinib synergize to induce cancer cell death through integrated ER stress, autophagy, and death receptor signaling.
- Autophagic degradation of HDACs is critical for enhancing MHCA expression, potentially improving response to checkpoint inhibitors.
- This combination therapy warrants further clinical investigation for renal carcinoma.
