No 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. Tar IntroductionMultiple myeloma (MM) is an incurable neoplasia of the terminally differentiated plasma cell and accounts for approximately 10% of all hematologic cancers. 1 Intrinsic genetic lesions as well as the bone marrow microenvironment contribute to the activation of proliferation and survival pathways, impairment of cell death mechanisms, and drug resistance. [2][3][4][5] Two pathways commonly dysregulated in MM involve activation of the serine/threonine kinase Akt (Akt pathway) and of the guanine nucleotide exchange factor RAS (RAS/MAPK pathway). The Akt pathway has repeatedly been found to be important for MM cell survival, 6,7 and we have recently shown that approximately 50% of primary MM samples display an Akt-dependent, phospho-Akt-positive phenotype. 7 Little is known about the mechanisms that lead to constitutive Akt activation in MM, but suitable genetic lesions, such as deletion of PTEN 8,9 or activating mutations of PIK3CA, 10,11 appear to be relatively rare in this disease. Conversely, the reported prevalence of activating mutations of K-and N-RAS in MM ranges from approximately 30% to 50% of patient samples. [12][13][14][15][16][17] The occurrence of RAS mutation appears independent of clinical stage, 13,17 but oncogenic RAS is associated with disease progression, aggressive phenotype, and shorter survival. 12,[17][18][19] It is also implied in the transition to MM because RAS mutations are rarely found in monoclonal gammopathy of undetermined significance. 13,16 However, analyses of the functional role of oncogenic RAS in MM are rare, mainly because of the entire lack of specific inhibitors. Prenylation blockers, such as farnesyltransferase inhibitors, had initially been developed to curb RAS signaling. Encouraging preclinical data, however, did not translate into clinical efficiency, and it has subsequently been shown that the observed effects were largely independent of oncoge...

Multiple myeloma (MM) is a largely incurable plasma cell malignancy with a poorly understood and heterogeneous clinical course. To identify potential, functionally relevant somatic mutations in MM, we performed whole-exome sequencing of five primary MM, corresponding germline DNA and six MM cell lines, and developed a bioinformatics strategy that also integrated published mutational data of 38 MM patients. Our analysis confirms that identical, recurrent mutations of single genes are infrequent in MM, but highlights that mutations cluster in important cellular pathways. Specifically, we show enrichment of mutations in adhesion molecules of MM cells, emphasizing the important role for the interaction of the MM cells with their microenvironment. We describe an increased rate of mutations in receptor tyrosine kinases (RTKs) and associated signaling effectors, for example, in EGFR, ERBB3, KRAS and MAP2K2, pointing to a role of aberrant RTK signaling in the development or progression of MM. The diversity of mutations affecting different nodes of a particular signaling network appears to be an intrinsic feature of individual MM samples, and the elucidation of intra- as well as interindividual redundancy in mutations that affect survival pathways will help to better tailor targeted therapeutic strategies to the specific needs of the MM patient.