Combination Treatment Targeting mTOR and MAPK Pathways Has Synergistic Activity in Multiple Myeloma

SIMPLE SUMMARY: Multiple myeloma (MM) is characterized by the clonal accumulation of abnormal plasma cells in the bone marrow. Although current treatments have improved the survival rates of patients with MM, MM remains incurable for most patients due to refractory disease and relapse. Thus, new therapeutic strategies are needed. Constitutive activation of the PI3K/AKT/mTOR signaling pathway has been identified in MM, leading to uncontrolled tumor growth and survival. In this study, we revealed that an inhibitor targeting mTOR with temsirolimus exhibited different anti-proliferation activity across our MM cell lines, regardless of their genetic features. Combination treatment of the mTOR inhibitor with a MEK inhibitor led to a synergistic anti-proliferation effect in MM cell lines. Thus, our study provides a rationale for future clinical trials of temsirolimus in MM patients as a component of combination therapy and suggests that MM cases with a high p-S6 but low p-AKT level could benefit from this combination. This was irrespective of cytogenetic features and reveals an additional way to classify MM cells. ABSTRACT: Multiple myeloma (MM) is an incurable, malignant B cell disorder characterized by frequent relapses and a poor prognosis. Thus, new therapeutic approaches are warranted. The phosphatidylinositol-3-kinase (PI3K) pathway plays a key role in many critical cellular processes, including cell proliferation and survival. Activated PI3K/AKT (protein kinases B)/mTOR (mammalian target of rapamycin) signaling has been identified in MM primary patient samples and cell lines. In this study, the efficacy of PI3K and mTOR inhibitors in various MM cell lines representing three different prognostic subtypes was tested. Whereas MM cell lines were rather resistant to PI3K inhibition, treatment with the mTOR inhibitor temsirolimus decreases the phosphorylation of key molecules in the PI3K pathway in MM cell lines, leading to G(0)/G(1) cell cycle arrest and thus reduced proliferation. Strikingly, the efficacy of temsirolimus was amplified by combining the treatment with the Mitogen-activated protein kinase kinase (MEK) inhibitor trametinib. Our findings provide a scientific rationale for the simultaneous inhibition of mTOR and MEK as a novel strategy for the treatment of MM.