American Association for Cancer Research
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Supplementary Text, Figure Legends, Figures S1-S12 from Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma

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posted on 2023-04-03, 21:22 authored by Banu Eskiocak, Elizabeth A. McMillan, Saurabh Mendiratta, Rahul K. Kollipara, Hailei Zhang, Caroline G. Humphries, Changguang Wang, Jose Garcia-Rodriguez, Ming Ding, Aubhishek Zaman, Tracy I. Rosales, Ugur Eskiocak, Michael P. Smith, Jessica Sudderth, Kakajan Komurov, Ralph J. Deberardinis, Claudia Wellbrock, Michael A. Davies, Jennifer A. Wargo, Yonghao Yu, Jef K. De Brabander, Noelle S. Williams, Lynda Chin, Helen Rizos, Georgina V. Long, Ralf Kittler, Michael A. White

Supplemental Figure S1. Integrative Analysis of Functional Genomics and Copy Number Variation in Melanoma Cells and Tissues, Supplemental Figure S2. Elastic Net Derived Biomarker Results for Melanoma Survival Genes and Detection of These Biomarkers in TCGA SKCM, Supplemental Figure S3. The SOX10 Regulatory Network Supporting Cell Autonomous Melanoma Cell Growth and Survival, Supplemental Figure S4. SOX10 Addiction Specifies Sensitivity of BRAF Mutant Melanomas to BRAF and MEK Inhibitors In Vitro, Related to Figure 1, Supplemental Figure S5. SOX10 Addiction Specifies Sensitivity of BRAF Mutant Melanomas to BRAF and MEK Inhibitors In Patients, Related to Figure 2, Supplemental Figure S6. Bicluster of melanoma cell lines and chemical compounds in McDermott/Benes GDSC dataset, Related to Figure 3, Supplemental Figure S7. Nomination of TBK1 as a Therapeutic Target for Drug-Resistant Melanoma, Related to Figure 3, Supplemental Figure S8. TBK1/IKKε-Addiction is Conserved In Vivo, Related to Figure 4, Supplemental Figure S9. TBK1/IKKε-Addiction Corresponds to a Cell Autonomous Innate Immune Melanoma Subtype, Related to Figure 5, Supplemental Figure S10. TBK1/IKKε Activate AKT and YAP to Support Survival of the Cell-autonomous Immune Melanoma Subtype, Related to Figure 6, Supplemental Figure S11. 13C glucose and 13C glutamine metabolism at 30m and 2h, Related to Figure 7 and Supplemental Fig. S7, Supplemental Figure S12. Distinct Epigenetic Cell Fate Programs Specify TBK1/IKKε Addiction, Related to Figure 7.


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Genomic diversity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathologic activation of the ERK1/2 pathway is a linchpin tumorigenic mechanism associated with the majority of primary and recurrent disease. Therefore, we sought to identify therapeutic targets that are selectively required for tumorigenicity in the presence of pathologic ERK1/2 signaling. By integration of multigenome chemical and genetic screens, recurrent architectural variants in melanoma tumor genomes, and patient outcome data, we identified two mechanistic subtypes of BRAFV600 melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKϵ inhibitors. Importantly, subtype membership can be predicted using a robust quantitative five-feature genetic biomarker. This biomarker, and the mechanistic relationships linked to it, can identify a cohort of best responders to clinical MEK inhibitors and identify a cohort of TBK1/IKBKϵ inhibitor–sensitive disease among nonresponders to current targeted therapy.Significance: This study identified two mechanistic subtypes of melanoma: (1) the best responders to clinical BRAF/MEK inhibitors (25%) and (2) nonresponders due to primary resistance mechanisms (9.9%). We identified robust biomarkers that can detect these subtypes in patient samples and predict clinical outcome. TBK1/IKBKϵ inhibitors were selectively toxic to drug-resistant melanoma. Cancer Discov; 7(8); 832–51. ©2017 AACR.See related commentary by Jenkins and Barbie, p. 799.This article is highlighted in the In This Issue feature, p. 783