Journal
CANCER DISCOVERY
Volume 4, Issue 1, Pages 69-79Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-13-0279
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Funding
- Stand Up To Cancer Innovative Research Grant
- Program of the Entertainment Industry Foundation [SU2C-AACR-IRG0409]
- National Cancer Institute [K22CA151638, 1R01CA176111]
- Burroughs Wellcome Fund
- Melanoma Research Alliance
- American Skin Association
- Sidney Kimmel Foundation for Cancer Research
- Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research
- Harry J. Lloyd Charitable Trust
- National Center for Advancing Translational Sciences UCLA CTSI [UL1TR000124]
- Ian Copeland Melanoma Fund
- Wesley Coyle Memorial Fund
- Seaver Institute
- American Association of Cancer Institutes
- California Institute for Regenerative Medicine
- National Health and Medical Research Council of Australia
- Translational Research Program of the Cancer Institute New South Wales
- NATIONAL CANCER INSTITUTE [P30CA016042, K22CA151638, R01CA176111, P01CA168585] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000124] Funding Source: NIH RePORTER
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BRAF inhibitor (BRAFi) therapy leads to remarkable anti melanoma responses, but the initial tumor shrinkage is commonly incomplete, providing a nidus for subsequent disease progression. Adaptive signaling may underlie early BRAFi resistance and influence the selection pattern for genetic variants, causing late, acquired resistance. We show here that BRAFi (or BRAFi + MEKi) therapy in patients frequently led to rebound phosphorylated AKT (p-AKT) levels in their melanomas early on-treatment. In cell lines, BRAFi treatment led to rebound levels of receptor tyrosine kinases (RTK; including PDGFR beta), phosphatidyl (3,4,5)-triphosphate (PIP3), pleckstrin homology domain recruitment, and p-AKT. PTEN expression limited this BRAFi-elicited PI3K-AKT signaling, which could be rescued by the introduction of a mutant AKT1 (Q79K) known to confer acquired BRAFi resistance. Functionally, AKT1(Q79K) conferred BRAFi resistance via amplification of BRAFi-elicited PI3K-AKT signaling. In addition, mitogen-activated protein kinase pathway inhibition enhanced clonogenic growth dependency on PI3K or AKT. Thus, adaptive or genetic upregulation of AKT critically participates in melanoma survival during BRAFi therapy. SIGNIFICANCE: This study provides a mechanistic link between early, adaptive and late, acquired BRAF inhibitor resistance in melanoma, with early BRAFi-induced signaling alterations shaping the subsequent evolutionary selective pressure. These findings argue for upfront, combined targeting of the mutant BRAF genotype and a pervasive drug-adaptive, AKT-dependent tumor response. (C) 2013 AACR.
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