Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma

Banu Eskiocak; Elizabeth McMillan; Saurabh Mendiratta; Rahul Kollipara; Hailei Zhang; Caroline Humphries; Changguang Wang; Jose Garcia-Rodriguez; Ming Ding; Aubhishek Zaman; Tracy 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 White

doi:10.1158/2159-8290.CD-16-0955

Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma

Banu Eskiocak, Elizabeth McMillan, Saurabh Mendiratta, Rahul Kollipara, Hailei Zhang, Caroline Humphries, Changguang Wang, Jose Garcia-Rodriguez, Ming Ding, Aubhishek Zaman, Tracy Rosales, Ugur Eskiocak, Michael P Smith, Jessica Sudderth, Kakajan Komurov, Ralph J DeBerardinis, Claudia Wellbrock, Michael A Davies, Jennifer A Wargo, Yonghao YuJef K De Brabander, Noelle S Williams, Lynda Chin, Helen Rizos, Georgina V. Long, Ralf Kittler, Michael White

Division of Cancer Sciences (L5)

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Abstract

Genomic diversity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathological 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 pathological ERK1/2 signaling. By integration of multi-genome chemical and genetic screens; recurrent architectural variants in melanoma tumor genomes; and patient outcome data; we identified 2 mechanistic subtypes of BRAF(V600) melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKE inhibitors. Importantly, subtype membership can be predicted using a robust quantitative 5-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/IKBKE inhibitor-sensitive disease among non-responders to current targeted therapy.

Original language	English
Journal	Cancer discovery
Early online date	28 Apr 2017
DOIs	https://doi.org/10.1158/2159-8290.CD-16-0955
Publication status	Published - 2017

Keywords

Journal Article

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/2159-8290.CD-16-0955

2159-8290.CD-16-0955.fullAccepted author manuscript, 3.06 MB

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Eskiocak, B., McMillan, E., Mendiratta, S., Kollipara, R., Zhang, H., Humphries, C., Wang, C., Garcia-Rodriguez, J., Ding, M., Zaman, A., Rosales, T., Eskiocak, U., Smith, M. P., Sudderth, J., Komurov, K., DeBerardinis, R. J., Wellbrock, C., Davies, M. A., Wargo, J. A., ... White, M. (2017). Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma. Cancer discovery. https://doi.org/10.1158/2159-8290.CD-16-0955

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title = "Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma",

abstract = "Genomic diversity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathological 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 pathological ERK1/2 signaling. By integration of multi-genome chemical and genetic screens; recurrent architectural variants in melanoma tumor genomes; and patient outcome data; we identified 2 mechanistic subtypes of BRAF(V600) melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKE inhibitors. Importantly, subtype membership can be predicted using a robust quantitative 5-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/IKBKE inhibitor-sensitive disease among non-responders to current targeted therapy.",

keywords = "Journal Article",

author = "Banu Eskiocak and Elizabeth McMillan and Saurabh Mendiratta and Rahul Kollipara and Hailei Zhang and Caroline Humphries and Changguang Wang and Jose Garcia-Rodriguez and Ming Ding and Aubhishek Zaman and Tracy Rosales and Ugur Eskiocak and Smith, {Michael P} and Jessica Sudderth and Kakajan Komurov and DeBerardinis, {Ralph J} and Claudia Wellbrock and Davies, {Michael A} and Wargo, {Jennifer A} and Yonghao Yu and {De Brabander}, {Jef K} and Williams, {Noelle S} and Lynda Chin and Helen Rizos and Long, {Georgina V.} and Ralf Kittler and Michael White",

note = "Copyright {\textcopyright}2017, American Association for Cancer Research.",

year = "2017",

doi = "10.1158/2159-8290.CD-16-0955",

language = "English",

journal = "Cancer discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research",

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Eskiocak, B, McMillan, E, Mendiratta, S, Kollipara, R, Zhang, H, Humphries, C, Wang, C, Garcia-Rodriguez, J, Ding, M, Zaman, A, Rosales, T, Eskiocak, U, Smith, MP, Sudderth, J, Komurov, K, DeBerardinis, RJ, Wellbrock, C, Davies, MA, Wargo, JA, Yu, Y, De Brabander, JK, Williams, NS, Chin, L, Rizos, H, Long, GV, Kittler, R & White, M 2017, 'Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma', Cancer discovery. https://doi.org/10.1158/2159-8290.CD-16-0955

TY - JOUR

T1 - Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma

AU - Eskiocak, Banu

AU - McMillan, Elizabeth

AU - Mendiratta, Saurabh

AU - Kollipara, Rahul

AU - Zhang, Hailei

AU - Humphries, Caroline

AU - Wang, Changguang

AU - Garcia-Rodriguez, Jose

AU - Ding, Ming

AU - Zaman, Aubhishek

AU - Rosales, Tracy

AU - Eskiocak, Ugur

AU - Smith, Michael P

AU - Sudderth, Jessica

AU - Komurov, Kakajan

AU - DeBerardinis, Ralph J

AU - Wellbrock, Claudia

AU - Davies, Michael A

AU - Wargo, Jennifer A

AU - Yu, Yonghao

AU - De Brabander, Jef K

AU - Williams, Noelle S

AU - Chin, Lynda

AU - Rizos, Helen

AU - Long, Georgina V.

AU - Kittler, Ralf

AU - White, Michael

PY - 2017

Y1 - 2017

N2 - Genomic diversity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathological 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 pathological ERK1/2 signaling. By integration of multi-genome chemical and genetic screens; recurrent architectural variants in melanoma tumor genomes; and patient outcome data; we identified 2 mechanistic subtypes of BRAF(V600) melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKE inhibitors. Importantly, subtype membership can be predicted using a robust quantitative 5-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/IKBKE inhibitor-sensitive disease among non-responders to current targeted therapy.

AB - Genomic diversity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathological 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 pathological ERK1/2 signaling. By integration of multi-genome chemical and genetic screens; recurrent architectural variants in melanoma tumor genomes; and patient outcome data; we identified 2 mechanistic subtypes of BRAF(V600) melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKE inhibitors. Importantly, subtype membership can be predicted using a robust quantitative 5-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/IKBKE inhibitor-sensitive disease among non-responders to current targeted therapy.

KW - Journal Article

U2 - 10.1158/2159-8290.CD-16-0955

DO - 10.1158/2159-8290.CD-16-0955

M3 - Article

C2 - 28455392

SN - 2159-8274

JO - Cancer discovery

JF - Cancer discovery

ER -

Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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