PT - JOURNAL ARTICLE AU - Diana M Carvalho AU - Sara Temelso AU - Alan Mackay AU - Helen N Pemberton AU - Rebecca Rogers AU - Ketty Kessler AU - Elisa Izquierdo AU - Lynn Bjerke AU - Janat Fazal Salom AU - Matthew Clarke AU - Yura Grabovska AU - Anna Burford AU - Nagore Gene Olaciregui AU - Jessica KR Boult AU - Valeria Molinari AU - Mariama Fofana AU - Paula Proszek AU - Elisabet F Potente AU - Kathryn R Taylor AU - Christopher Chandler AU - Bassel Zebian AU - Ranj Bhangoo AU - Andrew J Martin AU - Bassam Dabbous AU - Simon Stapleton AU - Samantha Hettige AU - Lynley V Marshall AU - Fernando Carceller AU - Henry C Mandeville AU - Sucheta J Vaidya AU - Safa Al-Sarraj AU - Leslie R Bridges AU - Robert Johnston AU - Jane Cryan AU - Michael Farrell AU - Darach Crimmins AU - John Caird AU - Jane Pears AU - Giulia Pericoli AU - Evelina Miele AU - Angela Mastronuzzi AU - Franco Locatelli AU - Andrea Carai AU - Simon P Robinson AU - Mike Hubank AU - Michelle Monje AU - Andrew S Moore AU - Timothy EG Hassall AU - Angel Montero Carcaboso AU - Christopher J Lord AU - Mara Vinci AU - Chris Jones TI - Drug screening linked to molecular profiling identifies novel dependencies in patient-derived primary cultures of paediatric high grade glioma and DIPG AID - 10.1101/2020.12.29.424674 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.12.29.424674 4099 - http://biorxiv.org/content/early/2020/12/30/2020.12.29.424674.short 4100 - http://biorxiv.org/content/early/2020/12/30/2020.12.29.424674.full AB - Paediatric high grade glioma and diffuse midline glioma (including DIPG) are comprised of multiple biological and clinical subgroups, the majority of which urgently require novel therapies. Patient-derived in vitro primary cell cultures represent potentially useful tools for mechanistic and preclinical investigation based upon their retention of key features of tumour subgroups under experimental conditions amenable to high-throughput approaches. We present 17 novel primary cultures derived from patients in London, Dublin and Belfast, and together with cultures established or shared from Barcelona, Brisbane, Rome and Stanford, assembled a panel of 52 models under 2D (laminin matrix) and/or 3D (neurospheres) conditions, fully credentialed by phenotypic and molecular comparison to the original tumour sample (methylation BeadArray, panel/exome sequencing, RNAseq). In screening a subset of these against a panel of ~400 approved chemotherapeutics and small molecules, we identified specific dependencies associated with tumour subgroups and/or specific molecular markers. These included MYCN-amplified cells and ATM/DNA-PK inhibitors, and DIPGs with PPM1D activating truncating mutations and inhibitors of MDM2 or PARP1. Specific mutations in PDGFRA were found to confer sensitivity to a range of RTK inhibitors, though not all such mutations conferred sensitivity to targeted agents. Notably, dual PDGFRA/FGFR and downstream pathway MEK inhibitors showed profound effects against both PDGFRA-sensitising mutant and FGFR1-dependent non-brainstem pHGG and DIPG. In total, 85% cells were found to have at least one drug screening hit in short term assays linked to the underlying biology of the patient’s tumour, providing a rational approach for individualised clinical translation.Competing Interest StatementThe authors have declared no competing interest.