Journal
CANCER RESEARCH
Volume 71, Issue 15, Pages 5067-5074Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-11-0140
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Funding
- Wesley Coyle Memorial Fund
- Ian Copeland Melanoma Fund
- Ruby Family Foundation
- Shirley and Ralph Shapiro, Louis Belley and Richard Schnarr Fund
- Seaver Institute
- Burroughs Wellcome Fund
- National Cancer Institute
- STOP CANCER Foundation
- V Foundation for Cancer Research
- Melanoma Research Foundation
- Melanoma Research Alliance
- American Skin Association
- Caltech-UCLA Joint Center for Translational Medicine
- UCLA Institute for Molecular Medicine
- Sidney Kimmel Foundation for Cancer Research
- Stand Up to Cancer/American Association for Cancer Research
- Fred L. Hartley Family Foundation
- Jonsson Cancer Center Foundation
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B-V600E-RAF mutation is found in 50% to 60% of melanomas, and the novel agents PLX4032/vemurafenib and GSK2118436 that inhibit the B-V600E-RAF kinase achieve a remarkable clinical response rate. However, as might be expected, acquired clinical resistance to these agents arises in most melanoma patients. PLX4032/vemurafenib resistance that arises in vivo in tumor matched short-term cultures or in vitro in melanoma cell lines is not caused by acquisition of secondary mutations in B-V600E-RAF but rather is caused by upregulating platelet-derived growth factor receptor beta (PDGFRb) or N-RAS which results in resistance or sensitivity to mitogen-activated protein (MAP)/extracellular signal-regulated (ERK; MEK) kinase inhibitors, respectively. In this study, we define a targeted combinatorial strategy to overcome PLX4032/vemurafenib resistance in melanoma cell lines or short-term culture where the resistance is driven by PDGFR beta upregulation, achieving synergistic growth inhibition and cytotoxicity. PDGFR beta-upregulated, PLX4032-resistant (PPRM) cell lines show dual phospho (p)-ERK and p-AKT upregulation, and their growth inhibitory responses to specific small molecule inhibitors correlated with p-ERK, p-AKT, and p-p70S6K levels. Coordinate inhibition of B-V600E-RAF inhibition and the RTK-PI3K-AKT-mTORC axis led to functionally significant rebound signaling, illustrating a robust and dynamic network connectivity. Combined B-RAF, phosphoinositide 3-kinase (PI3K), and mTORC1/2 inhibition suppressed both immediate early and delayed compensatory signaling, resulting in a highly synergistic growth inhibitory response but less efficient cytotoxic response. In contrast, the combination of MEK1/2, PI3K, and mTORC1/2 inhibitors consistently triggered apoptosis in a highly efficient manner. Together, our findings offer a rational strategy to guide clinical testing in preidentified subsets of patients who relapse during treatment with B-V600E-RAF inhibitors. Cancer Res; 71(15); 5067-74. (c) 2011 AACR.
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