Frequent functional activation of RAS signalling not explained by RAS/RAF mutations in relapsed/refractory multiple myeloma

Abstract

RAS mutations are frequent in relapsed/refractory multiple myeloma (RRMM) but functional study in primary samples is scanty. Herein, in primary myeloma plasma cells of 17 suspected RRMM, functional activation of RAS signalling was studied by Western blot of phosphorylated ERK1/2 (phospho-ERK1/2). Moreover, activating mutations in KRAS, NRAS, BRAF, and ALK were studied by PCR and bidirectional direct sequencing. Furthermore, methylation of negative RAS signalling regulator genes, RASSF1A and RASD1, were analyzed by methylation-specific PCR. As evidenced by phospho-ERK1/2 over-expression, functional RAS activation was detected in 12 (75.0%) RRMM. Of patients with functional RAS activation, sequencing data showed only seven (58.3%) patients with one each had NRAS Q61H, NRAS Q61K, KRAS G12D, KRAS G12V, KRAS G13D, KRAS Q61P, or BRAF V600E mutation, whereas five (41.7%) patients had no RAS/RAF mutation. Conversely, patients without functional RAS activation had no RAS/RAF mutation. Moreover, none of the patients with functional RAS activation had ALK mutations, or methylation of RASSF1A and RASD1. Collectively, functional activation of RAS signalling was present in majority of RRMM but only about half (58.3%) accountable by RAS/RAF mutations. If verified in larger studies, clinical investigations of MEK inhibitors are warranted regardless of RAS/RAF mutations.

KRAS, NRAS, and BRAF mutations in plasma cell myeloma at a single Korean institute

“…One study showed that RAS mutations appeared to be significantly associated with a favorable outcome [26]. Another study showed that functional activation of the RAS pathway was observed in 75% of patients with relapsed/refractory PCM and about half had RAS/RAF mutations [27]. In this study, we demonstrated that RAS/RAF mutations were associated with poor outcomes, such as a shorter PFS.…”

“…Aside from RAS/RAF mutations, a subgroup with BRAF V600E mutations also provided poor PFS compared to the wild-type RAS/RAF. Because the activation of the MAPK pathway via RAS/RAF mutations was concordant with the gene expression profile data of the same patients, inhibition of this signaling would be effective in this subgroup of patients [7,27,28]. Of them, BRAF has received considerable attention as a result of the success of targeted malignant melanoma therapy [29].…”

A proof-of-concept study for the pathogenetic role of enhancer hypomethylation of MYBPHL in multiple myeloma

“…Twelve patients with relapsed/refractory multiple myeloma (RRMM), including “relapsed” or “relapsed-and-refractory myeloma” cases were included for study of MYBPHL expression. Definition of relapsed myeloma is consistent with previously described 36 . This study was approved by the Institutional Review Board of Queen Mary Hospital.…”

Prognostic value of RASD1 transcript levels in adult Philadelphia-negative B-cell acute lymphoblastic leukemia

“…It has been reported that RASD1 played a role in regulating the development of tumors as a negative RAS signaling regulating gene [28]. RASD1 overexpression was reported to suppress cell growth in breast cancer and lung carcinoma cells, inhibit migration and invasion of glioma cells and participate in induced-apoptosis in breast cancer and prostate cancer cells [10,11,13,14,29,30].…”