Dietrich, P. and Kuphal, S. and Spruss, T. and Hellerbrand, C. and Bosserhoff, A. K. (2018) Wild-type KRAS is a novel therapeutic target for melanoma contributing to primary and acquired resistance to BRAF inhibition. ONCOGENE, 37 (7). pp. 897-911. ISSN 0950-9232, 1476-5594
Full text not available from this repository. (Request a copy)Abstract
Malignant melanoma reveals rapidly increasing incidence and mortality rates worldwide. By now, BRAF inhibition is the standard therapy for advanced melanoma in patients carrying BRAF mutations. However, only approximately 50% of melanoma patients harbor therapeutically attackable BRAF mutations, and overall survival after treatment with BRAF inhibitors is modest. KRAS (Kirsten Rat sarcoma) proteins are acting upstream of BRAF and have a major role in human cancer. Recent approaches awaken the hope to use KRAS inhibition (KRASi) as a clinical tool. In this study, we identified wild-type KRAS as a novel therapeutic target in melanoma. KRASi functions synergistically with BRAF inhibition to reduce melanoma proliferation and to induce apoptosis independently of BRAF mutational status. Moreover, acquired resistance to BRAF inhibitors in melanoma is dependent on dynamic regulation of KRAS expression with subsequent AKT and extracellular-signal regulated kinase activation and can be overcome by KRASi. This suggests KRASi as novel approach in melanoma-alone or in combination with other therapeutic regimes.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SMALL-MOLECULE INHIBITION; MEK INHIBITION; METASTATIC MELANOMA; PATHWAY; EXPRESSION; RAF; TUMORIGENESIS; VEMURAFENIB; ACTIVATION; EVOLUTION; |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 18 Mar 2020 09:06 |
| Last Modified: | 18 Mar 2020 09:06 |
| URI: | https://pred.uni-regensburg.de/id/eprint/15040 |
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