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Mutations in the RAS/MAPK Pathway Drive Replication Repair-Deficient Hypermutated Tumors and Confer Sensitivity to MEK Inhibition

BB. Campbell, MA. Galati, SC. Stone, AN. Riemenschneider, M. Edwards, S. Sudhaman, R. Siddaway, M. Komosa, NM. Nunes, L. Nobre, AS. Morrissy, M. Zatzman, M. Zapotocky, L. Joksimovic, SN. Kalimuthu, D. Samuel, G. Mason, E. Bouffet, DA....

. 2021 ; 11 (6) : 1454-1467. [pub] 20210209

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, multicentrická studie, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc22012414

Grantová podpora
R35 CA220500 NCI NIH HHS - United States
Canadian Institutes for Health Research

The RAS/MAPK pathway is an emerging targeted pathway across a spectrum of both adult and pediatric cancers. Typically, this is associated with a single, well-characterized point mutation in an oncogene. Hypermutant tumors that harbor many somatic mutations may obscure the interpretation of such targetable genomic events. We find that replication repair-deficient (RRD) cancers, which are universally hypermutant and affect children born with RRD cancer predisposition, are enriched for RAS/MAPK mutations (P = 10-8). These mutations are not random, exist in subclones, and increase in allelic frequency over time. The RAS/MAPK pathway is activated both transcriptionally and at the protein level in patient-derived RRD tumors, and these tumors responded to MEK inhibition in vitro and in vivo. Treatment of patients with RAS/MAPK hypermutant gliomas reveals durable responses to MEK inhibition. Our observations suggest that hypermutant tumors may be addicted to oncogenic pathways, resulting in favorable response to targeted therapies. SIGNIFICANCE: Tumors harboring a single RAS/MAPK driver mutation are targeted individually for therapeutic purposes. We find that in RRD hypermutant cancers, mutations in the RAS/MAPK pathway are enriched, highly expressed, and result in sensitivity to MEK inhibitors. Targeting an oncogenic pathway may provide therapeutic options for these hypermutant polyclonal cancers.This article is highlighted in the In This Issue feature, p. 1307.

2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Charbonneau Cancer Institute University of Calgary Calgary Alberta Canada

Department of Hematology Oncology Valley Children's Hospital Madera California

Department of Immunology University of Toronto Toronto Ontario Canada

Department of Laboratory Medicine and Pathobiology Faculty of Medicine University of Toronto Toronto Ontario Canada

Department of Medical Biophysics University of Toronto Toronto Ontario Canada

Department of Pathology Laboratory Medicine Program University Health Network and University of Toronto Toronto Ontario Canada

Department of Pediatric Hematology Oncology Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania

Developmental and Stem Cell Biology Program The Hospital for Sick Children Toronto Ontario Canada

Division of Hematology Oncology The Hospital for Sick Children Department of Pediatrics University of Toronto Toronto Ontario Canada

Division of Neurosurgery The Hospital for Sick Children Toronto Ontario Canada

Division of Oncology and Center for Childhood Cancer Research Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania Philadelphia Pennsylvania

Ontario Institute for Cancer Research Toronto Ontario Canada

Princess Margaret Cancer Centre University Health Network Toronto Ontario Canada

Program in Cell Biology The Hospital for Sick Children Toronto Ontario Canada

Program in Genetics and Genome Biology The Hospital for Sick Children Toronto Ontario Canada

The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto Ontario Canada

Zane Cohen Centre for Digestive Diseases Mount Sinai Hospital Toronto Ontario Canada

Citace poskytuje Crossref.org

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$a The RAS/MAPK pathway is an emerging targeted pathway across a spectrum of both adult and pediatric cancers. Typically, this is associated with a single, well-characterized point mutation in an oncogene. Hypermutant tumors that harbor many somatic mutations may obscure the interpretation of such targetable genomic events. We find that replication repair-deficient (RRD) cancers, which are universally hypermutant and affect children born with RRD cancer predisposition, are enriched for RAS/MAPK mutations (P = 10-8). These mutations are not random, exist in subclones, and increase in allelic frequency over time. The RAS/MAPK pathway is activated both transcriptionally and at the protein level in patient-derived RRD tumors, and these tumors responded to MEK inhibition in vitro and in vivo. Treatment of patients with RAS/MAPK hypermutant gliomas reveals durable responses to MEK inhibition. Our observations suggest that hypermutant tumors may be addicted to oncogenic pathways, resulting in favorable response to targeted therapies. SIGNIFICANCE: Tumors harboring a single RAS/MAPK driver mutation are targeted individually for therapeutic purposes. We find that in RRD hypermutant cancers, mutations in the RAS/MAPK pathway are enriched, highly expressed, and result in sensitivity to MEK inhibitors. Targeting an oncogenic pathway may provide therapeutic options for these hypermutant polyclonal cancers.This article is highlighted in the In This Issue feature, p. 1307.
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