Abstract
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.
Highlights
IntroductionThe rates of melanoma have been rapidly increasing (NIH, www.cancer.org). Melanoma is one of the most common cancers in young adults, and the risk for melanoma increases with age (NIH, www.cancer.org)
The rates of melanoma have been rapidly increasing (NIH, www.cancer.org)
We show that an in-depth resolution of individualized signaling signatures allows inhibiting the development of drug resistance and melanoma regrowth, by demonstrating that while melanoma models develop drug resistance several weeks following initial administration of the clinically used combination, dabrafenib+trametinib, individualized patient-specific signaling signature (PaSSS)-based drug combinations gain a longer-lasting effect and show high selectivity
Summary
The rates of melanoma have been rapidly increasing (NIH, www.cancer.org). Melanoma is one of the most common cancers in young adults, and the risk for melanoma increases with age (NIH, www.cancer.org). We design patient-specific targeted treatments for melanoma based on individualized alterations in signaling protein networks, rather than on genomic/protein biomarkers. Attempting to treat patients based on the identification of single biomarkers or signaling pathways may overlook tumor-specific molecular alterations that have evolved during the course of the disease, and the selected therapeutic regimen may lack long-term efficacy resulting from partial targeting of the tumor imbalance. We suggest exploring the cancer data space utilizing an information-theoretic approach that is based on surprisal analysis[9,10,11], to unbiasedly identify the altered signaling network structure that has emerged in every single tumor[9,10]
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