TY - JOUR T1 - Overcoming Resistance to BRAF<sup>V600E</sup> Inhibition in Melanoma by Deciphering and Targeting Personalized Protein Network Alterations JF - bioRxiv DO - 10.1101/2020.11.03.366245 SP - 2020.11.03.366245 AU - S. Vasudevan AU - E. Flashner-Abramson AU - I. Adesoji Adejumobi AU - D. Vilencki AU - S. Stefansky AU - A.M. Rubinstein AU - N. Kravchenko-Balasha Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/11/03/2020.11.03.366245.abstract N2 - BRAFV600E melanoma patients, despite initially responding to the clinically prescribed anti-BRAFV600E therapy, often relapse and their tumors develop drug resistance. While it is widely accepted that these tumors are originally driven by the BRAFV600E mutation, they often eventually diverge and become supported by various signaling networks. Therefore, patient-specific altered signaling signatures should be deciphered and treated individually.In this study, we design individualized melanoma combination treatments based on personalized network alterations. Using an information-theoretic approach, we compute high-resolution patient-specific altered signaling signatures. These altered signaling signatures each consist of several co-expressed subnetworks, which should all be targeted to optimally inhibit the entire altered signaling flux. Based on these data, we design smart, personalized drug combinations, often consisting of FDA-approved drugs. We validate our approach in vitro and in vivo showing that individualized drug combinations that are rationally based on patient-specific altered signaling signatures are more efficient than the clinically used anti-BRAFV600E or BRAFV600E/MEK targeted therapy. Furthermore, these drug combinations are highly selective, as a drug combination efficient for one BRAFV600E tumor is significantly less efficient for another, and vice versa. The approach presented herein can be broadly applicable to aid clinicians to rationally design patient-specific anti-melanoma drug combinations.Competing Interest StatementThe authors have declared no competing interest. ER -