A first-generation pediatric cancer dependency map.

Mar 25, 2021

Contributor: Neekesh V Dharia,Guillaume Kugener,Lillian M Guenther,Clare F Malone,Adam D Durbin,Andrew L Hong,Thomas P Howard,Pratiti Bandopadhayay,Caroline S Wechsler,Iris Fung,Allison C Warren,Joshua M Dempster,John M Krill-Burger,Brenton R Paolella,Phoebe Moh,Nishant Jha,Andrew Tang,Philip Montgomery,Jesse S Boehm,William C Hahn,Charles W M Roberts,James M McFarland,Aviad Tsherniak,Todd R Golub,Francisca Vazquez,Kimberly Stegmaier

A first-generation pediatric cancer dependency map.

Exciting therapeutic targets are emerging from CRISPR-based screens of high mutational-burden adult cancers. A key question, however, is whether functional genomic approaches will yield new targets in pediatric cancers, known for remarkably few mutations, which often encode proteins considered challenging drug targets. To address this, we created a first-generation pediatric cancer dependency map representing 13 pediatric solid and brain tumor types. Eighty-two pediatric cancer cell lines were subjected to genome-scale CRISPR-Cas9 loss-of-function screening to identify genes required for cell survival. In contrast to the finding that pediatric cancers harbor fewer somatic mutations, we found a similar complexity of genetic dependencies in pediatric cancer cell lines compared to that in adult models. Findings from the pediatric cancer dependency map provide preclinical support for ongoing precision medicine clinical trials. The vulnerabilities observed in pediatric cancers were often distinct from those in adult cancer, indicating that repurposing adult oncology drugs will be insufficient to address childhood cancers.

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About The Expert

Neekesh V Dharia

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Harvard Medical School, Boston, MA, USA.

Guillaume Kugener

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.

Lillian M Guenther

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Harvard Medical School, Boston, MA, USA.

Clare F Malone

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Harvard Medical School, Boston, MA, USA.

Adam D Durbin

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Harvard Medical School, Boston, MA, USA.

Department of Oncology, Comprehensive Cancer Center, St. Jude Children’s Research Hospital, Memphis, TN, USA.

Andrew L Hong

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Harvard Medical School, Boston, MA, USA.

Department of Pediatrics, Emory University and Department of Hematology and Oncology, Children’s Healthcare of Atlanta, Atlanta, GA, USA.

Thomas P Howard

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Harvard Medical School, Boston, MA, USA.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Pratiti Bandopadhayay

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Harvard Medical School, Boston, MA, USA.

Caroline S Wechsler

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Harvard Medical School, Boston, MA, USA.

Iris Fung

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Allison C Warren

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Joshua M Dempster

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

John M Krill-Burger

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Brenton R Paolella

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Phoebe Moh

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

University of Maryland, College Park, MD, USA.

Nishant Jha

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Andrew Tang

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Philip Montgomery

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Jesse S Boehm

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

William C Hahn

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Harvard Medical School, Boston, MA, USA.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Charles W M Roberts

Department of Oncology, Comprehensive Cancer Center, St. Jude Children’s Research Hospital, Memphis, TN, USA.

James M McFarland

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Aviad Tsherniak

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Todd R Golub

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Harvard Medical School, Boston, MA, USA.

Francisca Vazquez

Broad Institute of MIT and Harvard, Cambridge, MA, USA. vazquez@broadinstitute.org.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. vazquez@broadinstitute.org.

Kimberly Stegmaier

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. kimberly_stegmaier@dfci.harvard.edu.

Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA. kimberly_stegmaier@dfci.harvard.edu.

Broad Institute of MIT and Harvard, Cambridge, MA, USA. kimberly_stegmaier@dfci.harvard.edu.

Harvard Medical School, Boston, MA, USA. kimberly_stegmaier@dfci.harvard.edu.

References

PubMed