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Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
Cholesterol Regulates the Tumor Adaptive Resistance to MAPK Pathway Inhibition
Xu-Dong Wang1, Chiho Kim1, Yajie Zhang1
1Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, 75390 Texas, United States.
Abstract:
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. Here, we performed global tyrosine phosphoproteomic (pTyr) analyses and demonstrated that targeted MAPK signaling inhibition in melanoma leads to a profound remodeling of the pTyr proteome. Intriguingly, altered cholesterol metabolism might drive, in a coordinated fashion, the activation of these kinases. Indeed, we found an accumulation of intracellular cholesterol in melanoma cells (with BRAFV600E mutations) and non-small cell lung cancer cells (with KRASG12C mutations) treated with MAPK and KRASG12C inhibitors, respectively. Importantly, depletion of cholesterol not only prevents the feedback activation of pTyr signaling but also enhances the cytotoxic effects of MAPK pathway inhibitors, both in vitro and in vivo. 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.
Insights
Targeted MAPK pathway inhibitors can cause drug resistance by altering cholesterol metabolism. Lowering cholesterol levels can enhance cancer treatment effectiveness and durability in MAPK-driven tumors.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Targeted therapies inhibiting the MAPK pathway show promise in cancer treatment.
- Drug resistance, driven by adaptive tumor responses, remains a significant clinical challenge.
- Bypass mechanisms activated during resistance complicate combination therapy design.
Purpose of the Study:
- To investigate the molecular mechanisms underlying adaptive resistance to MAPK pathway inhibitors.
- To explore the role of cholesterol metabolism in mediating resistance to targeted cancer therapies.
- To evaluate the therapeutic potential of combining MAPK inhibitors with cholesterol-lowering agents.
Main Methods:
- Global tyrosine phosphoproteomic (pTyr) analyses were performed on cancer cells treated with MAPK pathway inhibitors.
- Intracellular cholesterol levels were measured in melanoma and non-small cell lung cancer cells.
- The effects of cholesterol depletion on signaling pathways and cell viability were assessed in vitro and in vivo.
Main Results:
- Targeted MAPK inhibition induced significant remodeling of the tyrosine phosphoproteome.
- Intracellular cholesterol accumulated in cancer cells treated with MAPK or KRAS inhibitors.
- Cholesterol depletion reversed feedback activation of signaling pathways and enhanced drug cytotoxicity.
- Combined treatment demonstrated improved efficacy in preclinical models.
Conclusions:
- Cholesterol metabolism plays a critical role in the adaptive resistance to MAPK pathway inhibitors.
- Targeting cholesterol could be a viable strategy to overcome resistance and improve outcomes in MAPK-driven cancers.
- Combination therapy with MAPK inhibitors and cholesterol-lowering agents may offer a more durable and effective treatment approach.
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