Combined targeting of MEK/MAPK and PI3K/Akt signalling in multiple myeloma

Abstract

SummarySo-called RAS-dependent pathways, such as those signalling via mitogenactivated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K)/Akt, are implicated in proliferation and survival of multiple myeloma (MM) cells. However, the effects of their combined blockade and its potential therapeutic utility for the treatment of RAS-mutated MM have not systematically been analysed. Here, we tested the functional consequences of single versus combined inhibition of the MEK/MAPK and PI3K/Akt pathways in a large series of primary MM samples (n = 55) and MM cell lines (n = 11). Additionally, the anti-myeloma activity of different treatments was analysed with respect to the RAS mutation status. PI3K/Akt blockade was generally more pro-apoptotic than blockade of MEK/MAPK both in cell lines and in primary MM samples. Simultaneous blockade of both pathways led to significantly enhanced anti-myeloma activity in 75% of primary MM samples, whereas the remainder was largely resistant. Resistance to combination blockade was exclusively observed in RAS wildtype cases, whereas sensitivity was noted in RAS wildtype and in RAS mutated MM. These results suggest that oncogenic RAS is a predictor of sensitivity to combination treatment with PI3K/Akt and MEK/MAPK inhibitors and that such an approach might therefore be beneficial for this genetically well-defined subgroup of MM patients.

Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes

“…BRAF or MEK inhibitors are already in clinical testing and seem promising. 31,32,49,50 NRAS and KRAS mutations occurred mostly within known activating hotspots of the gene, and 4 of 9 BRAF mutations were druggable p.Val600Glu. However, BRAF mutations with paradoxical activation of the pathway via c-raf were also found in 4 patients, and in 1 of them (patient #41), 2 simultaneous BRAF mutations were identified: 1 at amino acid position 499 that has been suggested to be ERK activating and has been described in cardiofaciocutaneous syndrome, 51 and 1 in p.Glu695Lys, located in the protein kinase domain within the activator loop, previously reported in skin cutaneous melanoma.…”

PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1

“…Our finding that AKT inhibitors do not suppress ERK and are inferior to PI3K inhibitors in terms of induction of the proapoptotic molecule BIM and apoptosis suggests that PI3K inhibitors may have superior antitumor activity compared with AKT inhibitors for certain cancers. Previous studies have demonstrated that combined inhibition of both PI3K/AKT and ERK pathways are substantially more effective in promoting durable tumor regression in other cancer models (25)(26)(27)(28)(29)(30). However, the functional differences between PI3K and AKT inhibitors may extend beyond the regulation of P-Rex1 and ERK signaling.…”

The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma

“…9,10 The PI3K/AKT pathway activation in MM is mostly related to signaling from major growth factor receptors such as insulin-like growth factor-1 or interleukin-6. [11][12][13] This dependence on the PI3K/AKT pathway is suggested by the observation that inhibition of the pathway with PI3K inhibitors and/or mTOR inhibitors has been shown to induce apoptosis in myeloma cell lines and in tumor cells derived from patients. 11,14 Afuresertib is a reversible, ATP-competitive, oral, low-nanomolar, pan-AKT kinase inhibitor.…”