RT Journal Article
SR Electronic
T1 A functional pre-screening platform for identifying points of vulnerability in the cell death map of human melanoma tumors
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.11.377671
DO 10.1101/2020.11.11.377671
A1 Naama Pnina Dekel-Bird
A1 Shani Bialik
A1 Orit Itzhaki
A1 Tomer Meir Salame
A1 Naama Yaeli-Slonim
A1 Vered Levin-Salomon
A1 Santosh Kumar Dasari
A1 Michal Besser
A1 Adi Kimchi
YR 2020
UL http://biorxiv.org/content/early/2020/11/11/2020.11.11.377671.abstract
AB Targeted drug therapy in melanoma patients carrying the BRAF V600E mutation provides temporary remission, often followed by relapse due to acquired drug resistance. Here we propose a functional approach to circumvent drug resistance by applying a personalized prescreening platform that maps points of vulnerability in each tumor, prior to drug treatment. This platform applies siRNAs targeting 81 apoptosis, autophagy and programmed necrosis genes in patient tumor cell cultures, identifying genes whose targeting maximizes cell killing by short-term BRAF inhibition. Melanoma tumors displayed large heterogeneity in the number and identities of soft-spots, providing different tumor-specific functional death signatures. The soft-spots were targeted by replacing functional siRNAs with small compound inhibitors for long-term treatment in combination with vemurafenib. This strategy reduced the number of drug-tolerant persister cells surviving treatment, and most importantly, the number of drug-resistant foci. Thus, prescreening melanoma tumors for soft-spots within the cell death network may enhance targeted drug therapy before resistance emerges, thereby reducing the odds of developing drug-resistant mutations, and preventing tumor relapse.Competing Interest StatementThe authors have declared no competing interest.