Cholesterol Regulates the Tumor Adaptive Resistance to MAPK Pathway Inhibition
Source : https://pubs.acs.org/doi/10.1021/acs.jproteome.1c00550
Although targeted MAPK pathway inhibition has achieved remarkable patient responses in many cancers, the development of resistance has remained a critical challenge. Adaptive tumor response underlies the drug resistance. Furthermore, such bypass mechanisms often lead to the activation of many pro-survival kinases, which complicates the rational design of combination therapies.
Together, our findings suggest that cholesterol contributes to the tumor adaptive response upon targeted MAPK pathway inhibitors. These results also suggest that MAPK pathway inhibitors could be combined with cholesterol-lowering agents to achieve a more complete and durable response in tumors with hyperactive MAPK signaling.
• Source: Journal of Proteome Research
• Conclusion/Relevance: “[W]e performed a comprehensive characterization of the remodeling of the p-Tyr proteome in melanoma cells treated with various MAPK pathway inhibitors. We showed that the blockade of MAPK signaling leads to the accumulation of cholesterol, which serves as a contributing factor to control the coordinated activation of multiple RTKs [receptor tyrosine kinases]. Importantly, the combination of cholesterol-lowering agents and MAPK pathway inhibitors overcomes the adaptive response in melanoma and NSCLC in cell culture and xenograft models. Because both atorvastatin and several MAPK pathway inhibitors (e.g., PLX4032 and AMG510) have already been approved by the FDA, this provides an actionable combination therapy that can be rapidly translated and tested in clinical studies.”
• Targeted MAPK pathway inhibition has attained strong patient responses in various cancers. Nevertheless, resistance has continued to be a challenge, with adaptive tumor response underpinning drug resistance. Bypass mechanisms often result in the activation of many pro-survival kinases, which confounds the design of combination therapies.
• While seeking a molecular switch that mediates the coordinated activation of multiple RTKs, the researchers pinpointed a cholesterol binding motif that is shared by various tyrosine kinases
• In the current study, researchers performed global tyrosine phosphoproteomic (pTyr) analyses and showed that targeted MAPK signaling inhibition in melanoma resulted in remodeling of the pTyr proteome. Altered cholesterol metabolism could activate these kinases in a coordinated way. .
• “Taken together, our results demonstrate cholesterol as the central signaling hub that controls the activation of bypass signaling during MAPK pathway inhibition. The potential regulatory mechanisms that lead to cholesterol accumulation under these conditions warrant further investigation,” wrote the authors.