KRAS/NRAS/BRAF Mutations as Potential Targets in Multiple Myeloma

Sergiu Pasca; Ciprian Tomuleasa; Patric Teodorescu; Gabriel Ghiaur; Delia Dima; Vlad Moisoiu; Cristian Berce; Cristina Stefan; Aaron Ciechanover; Herman Einsele

doi:10.3389/fonc.2019.01137

KRAS/NRAS/BRAF Mutations as Potential Targets in Multiple Myeloma

Front Oncol. 2019 Oct 24:9:1137. doi: 10.3389/fonc.2019.01137. eCollection 2019.

Authors

Sergiu Pasca¹, Ciprian Tomuleasa^{1

2

3}, Patric Teodorescu^{1

2}, Gabriel Ghiaur⁴, Delia Dima², Vlad Moisoiu¹, Cristian Berce¹, Cristina Stefan⁵, Aaron Ciechanover⁶, Herman Einsele⁷

Affiliations

¹ Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
² Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania.
³ Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
⁴ Department of Leukemia, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, United States.
⁵ African Organisation for Research and Training in Cancer, Cape Town, South Africa.
⁶ The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
⁷ Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.

Abstract

In multiple myeloma the mutational profile is mainly represented by translocations involving chromosome 14 and by single nucleotide mutations, frequently involving genes implicated in the mitogen activated protein kinase (MAPK) pathway, as KRAS, NRAS, and, less frequently, BRAF. Because KRAS/NRAS/BRAF mutations are associated with a higher number of mutations per patient, we hypothesize that this group of patients could benefit from therapy with checkpoint inhibitors because of the higher frequency of neo-antigens that this group would present. This might also true for IMiD therapy, because of their activatory effect on T cells. Because, KRAS/NRAS/BRAF are members of the MAPK pathway, this subgroup of patients would also benefit from inhibitors of MAPK, either directly on the specific mutation or through downstream targeting of MEK1/2 or ERK1/2 to account for a possible compensatory collateral signaling that might activate as response to upstream inhibition.

Keywords: BRAF; KRAS; NRAS; multiple myeloma; therapeutics.