Inactivation of Receptor Tyrosine Kinases Overcomes Resistance to Targeted B-RAF Inhibitors in Melanoma Cell Lines

Ryabaya, Oxana; Malysheva, A. A.; Khochenkova, Yu. A.; Solomko, Elico; Khochenkov, Dmitry

doi:10.1134/s0026893318020115

Cited by 3 publications

(2 citation statements)

References 30 publications

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“…We utilized a quantitative mass spectrometry-based proteomic strategy to comprehensively monitor the dynamic remodeling of the p-Tyr proteome. Indeed, our findings aligned well with the previous studies, with the identification of activated tyrosine kinases (e.g., PDGF, JAK/STAT3, VEGF, c-kit et al ) in melanoma cells treated with various MAPK inhibitors (9, 37–40). Among these pathways, the JAK/STAT3 signaling axis has been well documented as a critical mediator of the adaptive tumor response (18, 41–43).…”

Section: Discussionsupporting

confidence: 92%

Quantitative Tyr Phosphoproteomic Analyses Identify Cholesterol as a Master Regulator of the Tumor Adaptive Resistance to MAPK Inhibition

Wang

Kim

Zhang

et al. 2021

Preprint

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Although targeted inhibition of the MAPK pathway has achieved remarkable patient responses in many cancers with MAPK hyperactivation, the development of resistance has remained a critical challenge. Besides genomic resistance mechanisms, adaptive tumor response also underlies the resistance to targeted MAPK inhibitors. It is being increasingly appreciated that 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 inhibition of MAPK signaling in melanoma cells leads to a profound remodeling of the pTyr proteome. Intriguingly, many of these kinases contain a cholesterol binding motif, suggesting that altered cholesterol metabolism might drive, in a coordinated fashion, the activation of these kinases. Indeed, we found a dramatic 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 prevented the MAPK inhibition-induced feedback activation of pTyr singling but also enhanced the cytotoxic effects of MAPK inhibitors, both in vitro and in vivo. Taken together, our findings provide the evidence suggesting that cholesterol functions as a master regulator of the tumor adaptive response to targeted MAPK inhibitors. These results also suggest that MAPK inhibitors could be combined with cholesterol-lowering agents to achieve a more complete and durable response in tumors with hyperactive MAPK signaling.

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Section: Discussionsupporting

confidence: 92%

Quantitative Tyr Phosphoproteomic Analyses Identify Cholesterol as a Master Regulator of the Tumor Adaptive Resistance to MAPK Inhibition

Wang

Kim

Zhang

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Indeed, our findings aligned well with the previous studies, with the identification of activated tyrosine kinases (e.g., PDGF, JAK/STAT3, VEGF, c-kit, etc.) in melanoma cells treated with various MAPK pathway inhibitors. ,− Among these pathways, the JAK/STAT3 signaling axis has been well documented as a critical mediator of the adaptive tumor response. − Activation of JAK/STAT3 signaling is an important adaptive resistance mechanism to EGFR tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC) . Our data suggest that JAK/STAT3 could also be a bypass mechanism that is relevant to MAPK-inhibited melanoma cells.…”

Section: Discussionmentioning

confidence: 86%

Cholesterol Regulates the Tumor Adaptive Resistance to MAPK Pathway Inhibition

et al. 2021

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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 BRAF V600E mutations) and non-small cell lung cancer cells (with KRAS G12C mutations) treated with MAPK and KRAS G12C 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.

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Expanding the understanding of the heterogeneous nature of melanoma with bioinformatics and disorder-based proteomics

Djulbegovic

Uversky

2020

International Journal of Biological Macromolecules

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Inactivation of Receptor Tyrosine Kinases Overcomes Resistance to Targeted B-RAF Inhibitors in Melanoma Cell Lines

Cited by 3 publications

References 30 publications

Quantitative Tyr Phosphoproteomic Analyses Identify Cholesterol as a Master Regulator of the Tumor Adaptive Resistance to MAPK Inhibition

Quantitative Tyr Phosphoproteomic Analyses Identify Cholesterol as a Master Regulator of the Tumor Adaptive Resistance to MAPK Inhibition

Cholesterol Regulates the Tumor Adaptive Resistance to MAPK Pathway Inhibition

Expanding the understanding of the heterogeneous nature of melanoma with bioinformatics and disorder-based proteomics

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