A first-generation pediatric cancer dependency map

Abstract

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 adult models. Findings from the Pediatric Cancer Dependency Map provide pre-clinical support for ongoing precision medicine clinical trials. The vulnerabilities seen in pediatric cancers were often distinct from adult, indicating that repurposing adult oncology drugs will be insufficient to address childhood cancers.

Automated compound testing in zebrafish xenografts identifies combined MCL-1 and BCL-XL inhibition to be effective against Ewing sarcoma

“…Cancer cells seem to be more primed for apoptosis than most healthy cells and often depend on anti-apoptotic proteins for survival 29 . In Ewing sarcoma, MCL-1 has been identified as a dependency protein in CRISPR screens, which is in good agreement with our drug testing results 30,31 .…”

TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma

“…Genome-scale CRISPR-Cas9 screens have revealed genetic dependencies in multiple cancers ( Behan et al., 2019 ; Tsherniak et al., 2017 ) offering inroads into identifying therapeutic targets for diseases with a paucity of recurrently mutated genes, such as pediatric cancers. Strikingly, we identified TRIM8 as a top enriched dependency in Ewing sarcoma ( Dharia et al., 2021 ) in two independent CRISPR screens using the GeCKO library ( Sanjana et al., 2014 ), where 43 cancer cell lines were screened, and the Avana library ( Doench et al., 2016 ), where over 700 cancer cell lines were screened ( Figures 1 F–1I). The TRIM8 dependency was independent of the ETS fusion partner; EWS/FLI- , EWS/ERG -, and EWS/FEV1 -positive Ewing sarcoma cell lines were all dependent on TRIM8 ( Figures 1 F and 1G).…”

SIX1 Reprograms Myogenic Transcription Factors to Maintain the Rhabdomyosarcoma undifferentiated state

“…Using a 1-4 scoring system of nuclear immunohistochemical staining, we detected strong nuclear SIX1 staining in the ERMS/Fusion-Negative and ARMS/Fusion-Positive tumor sections (18% and 29% with IHC staining scores ≥ 2, respectively) compared to normal skeletal muscle control sections (0% with IHC staining score ≥2) (Figure 1B-C). To further determine if SIX1 has a functional role in RMS, we next examined data from the Broad and Sanger Institutes’ exome-wide CRISPR-Cas9 knockout (KO) screening dataset 18 . In the 869 cell lines tested in the CRISPR-Cas9 screen, we observed that the 10 RMS cell lines used in the screen exhibited both high SIX1 mRNA expression and high SIX1 gene dependency (Figure 1D).…”