Mutated RAS and constitutively activated Akt delineate distinct oncogenic pathways, which independently contribute to multiple myeloma cell survival
- 10 February 2011
- journal article
- Published by American Society of Hematology in Blood
- Vol. 117 (6), 1998-2004
- https://doi.org/10.1182/blood-2010-05-284422
Abstract
We have recently shown that approximately half of primary multiple myeloma (MM) samples display constitutive Akt activity, which disposes them for sensitivity to Akt inhibition. The Akt pathway counts among the signaling conduits for oncogenic RAS and activating mutations of K- and N-RAS frequently occur in MM. We therefore analyzed the relation between RAS mutation and Akt dependency in biopsies and CD138-purified cells from MM patients (n = 65) and the function of oncogenic RAS for MM cell survival in a range of MM cell lines with differing RAS status. Whereas RAS mutations do not predict Akt dependency, oncogenic RAS retains an important role for MM cell survival. Knockdown of either K- or N-RAS strongly decreased the viability of MM cells that harbored the respective oncogenic isoform, whereas ablation of wild-type RAS isoforms had little or no effect. Silencing of oncogenic RAS did not affect the Akt pathway, again indicating lack of a direct link. Combined inhibition of RAS and Akt strongly enhanced MM cell death. These data suggest that oncogenic RAS and Akt may independently contribute to MM cell survival. Targeting of both pathways could provide an attractive therapeutic strategy for patients with oncogenic RAS and dysregulated Akt signaling.Keywords
This publication has 41 references indexed in Scilit:
- Classical and/or alternative NF-κB pathway activation in multiple myelomaPublished by American Society of Hematology ,2010
- Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1Nature, 2009
- A Gene Expression Signature Associated with “K-Ras Addiction” Reveals Regulators of EMT and Tumor Cell SurvivalCancer Cell, 2009
- Bone marrow microenvironment and the identification of new targets for myeloma therapyLeukemia, 2008
- Multiple myelomaBlood, 2008
- Genetic events in the pathogenesis of multiple myelomaBest Practice & Research Clinical Haematology, 2007
- Ras isoform abundance and signalling in human cancer cell linesOncogene, 2007
- Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myelomaBlood, 2005
- Combined disruption of both the MEK/ERK and the IL-6R/STAT3 pathways is required to induce apoptosis of multiple myeloma cells in the presence of bone marrow stromal cellsBlood, 2004
- Multiple myeloma: evolving genetic events and host interactionsNature Reviews Cancer, 2002