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10.1038/nature24037 http://scihub22266oqcxt.onion/10.1038/nature24037 C5640985!5640985!28976960     free     free     free Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Nature 2017 ; 550 (7675): 270-4 Nephropedia Template TP {{tp|p=28976960|t=2017. Cancer Drug Addiction is Relayed by an ERK2-Dependent Phenotype Switch |pdf=|usr=}}{{28976960}} gab.com Text Cancer Drug Addiction is Relayed by an ERK2-Dependent Phenotype Switch JO: Nature http://www.kidney.de/pget.php?&tw=1&pmid=28976960 #FOAvip Drug addiction denotes the dependency of tumors on the same therapeutic drugs to which they have acquired resistance. Observations from cultured cells1?3, animal models4 and patients5?7 raise the possibility that cancer drug addiction can instigate a potential cancer vulnerability, which may be used therapeutically. However, for this trait to become of clinical interest, it is imperative to first define the underlying mechanism. Therefore, we performed an unbiased CRISPR-Cas9 knockout screen to functionally mine the genome of melanoma cells that are both resistant and addicted to BRAF inhibition for ?addiction genes?. Here, we describe a signaling pathway comprising ERK2, JUNB and FRA1, disruption of which allows tumor cells to reverse addiction and survive upon treatment discontinuation. This occurred both in culture and mice, and was irrespective of the acquired drug resistance mechanism. In melanoma and lung cancer cells, death induced by drug withdrawal was preceded by a specific ERK2-dependent phenotype switch, alongside transcriptional reprogramming reminiscent of EMT. In melanoma, this caused shutdown of the lineage survival oncoprotein MITF, restoration of which reversed both phenotype switching and drug addiction-associated lethality. In melanoma patients who had progressed on BRAF inhibition, treatment cessation was followed by increased expression of the phenotype switch-associated receptor tyrosine kinase AXL. Drug discontinuation synergized with the melanoma chemotherapeutic dacarbazine by further suppressing MITF and its prosurvival target BCL2 while inducing DNA damage. Our results uncover a pathway driving cancer drug addiction, which may guide alternating therapeutic strategies for enhanced clinical responses of drug-resistant cancers. Twit Text FOAVip Cancer Drug Addiction is Relayed by an ERK2-Dependent Phenotype Switch ????Nature http://www.kidney.de/pget.php?&tw=1&pmid=28976960 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=28976960 #FOAvip English Wikipedia <ref>{{Cite pmid|28976960}}</ref> Cancer Drug Addiction is Relayed by an ERK2-Dependent Phenotype Switch #MMPMID28976960 Kong X; Kuilman T; Shahrabi A; Boshuizen J; Kemper K; Song JY; Niessen HW; Rozeman EA; Geukes Foppen MH; Blank CU; Peeper DS Nature 2017[Oct]; 550 (7675): 270-4 PMID28976960show ga Drug addiction denotes the dependency of tumors on the same therapeutic drugs to which they have acquired resistance. Observations from cultured cells1?3, animal models4 and patients5?7 raise the possibility that cancer drug addiction can instigate a potential cancer vulnerability, which may be used therapeutically. However, for this trait to become of clinical interest, it is imperative to first define the underlying mechanism. Therefore, we performed an unbiased CRISPR-Cas9 knockout screen to functionally mine the genome of melanoma cells that are both resistant and addicted to BRAF inhibition for ?addiction genes?. Here, we describe a signaling pathway comprising ERK2, JUNB and FRA1, disruption of which allows tumor cells to reverse addiction and survive upon treatment discontinuation. This occurred both in culture and mice, and was irrespective of the acquired drug resistance mechanism. In melanoma and lung cancer cells, death induced by drug withdrawal was preceded by a specific ERK2-dependent phenotype switch, alongside transcriptional reprogramming reminiscent of EMT. In melanoma, this caused shutdown of the lineage survival oncoprotein MITF, restoration of which reversed both phenotype switching and drug addiction-associated lethality. In melanoma patients who had progressed on BRAF inhibition, treatment cessation was followed by increased expression of the phenotype switch-associated receptor tyrosine kinase AXL. Drug discontinuation synergized with the melanoma chemotherapeutic dacarbazine by further suppressing MITF and its prosurvival target BCL2 while inducing DNA damage. Our results uncover a pathway driving cancer drug addiction, which may guide alternating therapeutic strategies for enhanced clinical responses of drug-resistant cancers. äCancer Drug Addiction is Relayed by an ERK2-Dependent Phenotype Switch(epmc).pdf DeepDyve Pubget Overpricing