Wild-type KRAS is a novel therapeutic target for melanoma contributing to primary and acquired resistance to BRAF inhibition

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.

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Abbreviations

AKT:

v-akt murine thymoma viral oncogene

BRAF:

v-Raf murine sarcoma viral oncogene homolog B

BRAFi:

BRAF inhibition/inhibitor

CTR:

control

DR:

Deltarasin

ERK:

extracellular-signal regulated kinase

KR:

KRAS (Kirsten Rat sarcoma)

KRASi:

KRAS inhibition/inhibitor

MAPK:

mitogen-activated protein kinase

MEK:

mitogen-activated protein kinase kinase

MEKi:

MEK inhibition/inhibitor

NRAS:

neuroblastoma RAS viral oncogene homolog

PI3K:

phosphatidylinositol-4,5-bisphosphate 3-kinase

PLX:

PLX-4032 (Vemurafenib).

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Acknowledgements

This work was supported by the German Research Association (DFG) (Research Training Group ‘RTG 1962/1’, University of Erlangen), the German Cancer Aid (Deutsche Krebshilfe), the Bavarian Research Network for Molecular Biosystems (BioSysNet) and the Interdisciplinary Center for Clinical Research (IZKF) Erlangen (J55, to PD and D24, to AB). We thank Meenhard Herlyn (The Wistar Institute, Philadelphia, USA) for providing the resistant cell lines. Furthermore, we thank Rudolf Jung, Annette Serwotka and Darleen Schönwälder for technical assistance.

Author contributions

PD, CH and AKB conceived the project, analyzed the data and wrote the paper. PD designed and performed most of the experiments. TS helped in planning and performing mouse experiments. SK contributed to data analysis and manuscript creation.

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Correspondence to A K Bosserhoff.

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Dietrich, P., Kuphal, S., Spruss, T. et al. Wild-type KRAS is a novel therapeutic target for melanoma contributing to primary and acquired resistance to BRAF inhibition. Oncogene 37, 897–911 (2018). https://doi.org/10.1038/onc.2017.391

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