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Our analysis demonstrates the necessity of mapping the intact cell death pathways that can be activated in each individual tumor.The molecular and phenotypic analysis of the twelve early passage melanoma cell lines derived from individual patient tumors showed different types of responses to purchase ENMD2076 vemurafenib treatment, and the siRNA perturbations indicated different functional death signatures in each cell line.This could reflect the fact that the BRAFERK signaling axis can be connected to different cellular processes, and thus its inhibition will have divergent effects on pathways controlling cell growth and death, both caspasedependent and independent.It was not surprising that many apoptotic regulators emerged as softspots, as vemurafenib treatment has been documented to activate apoptosis in many cases. Yet both the diversity of the softspots, and the unexpected emergence of some proapoptotic proteins among them, underscore the importance of conducting unbiased personalized screens to identify the best means of activating the apoptosis module during vemurafenib treatment.However, choosing the right inhibitor that would be most effective is still a challenge; the analysis presented here shows that different melanomas respond differently to the range of BH mimetics currently available.In addition to apoptosis, Targetmol’s ENMD2076 autophagy was also found to play a role in the survival of melanoma cell lines.The copyright holder for this preprint is the authorfunder.pancreatic cancer. This led to the suggestion that autophagy helps cells cope with the stress induced by drug treatment, and therefore blocking autophagy removes this coping mechanism and enhances the death response.Most of the autophagic hits fell within the ubiquitinlike conjugation pathway that executes the membrane elongation steps of autophagy.Upstream regulators were less prominent; this may be due to the abundance of signaling pathways that converge on the initiation stages of autophagy, redundancy among these regulators, the multiple sources for phagophore membrane initiation, andor the presence of noncanonical signaling pathways that can occur independently of the VPS PIK lipid kinase and ULK complexes.The ubiquitinlike conjugation step, in contrast, may serve as a limiting process for the continuation of autophagy.Of note, autophagy inhibitors in use in the clinic to date, such as chloroquine and HCQ, are not specific for the autophagy process.Preclinical attempts to develop more specific inhibitors have focused on kinases such as VPS. Our study, however, indicates that these upstream targets may not be ratelimiting and thus not the best candidates for blocking this survival pathway in melanoma, but rather, drug design should focus on the ubiquitinlike conjugation step.As in the case of the BCL family inhibitors, the cell death signature data indicates that inhibiting autophagy is not effective in all melanoma tumors; our study suggests that prescreening tumor responses to vemurafenib can predict the effectiveness of autophagic inhibitors as a viable cotreatment strategy.Another prominent hit was DAPK, detected as a softspot in half of the cell lines tested.DAPK is a member of the deathassociated protein kinase family.It was found to have roles in induction of both apoptosis. The copyright holder for this preprint is the authorfunder.tumor suppressive properties of the DAPK family and their ability to promote cell death.Our results suggest that DAPK acts as a prosurvival protein in melanoma and therefore is a promising, relatively novel drug target.

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