RAL GTPases mediate multiple myeloma cell survival and are activated independently of oncogenic RAS

Oncogenic RAS provides crucial survival signaling for up to half of multiple myeloma (MM) cases, but has so far remained a clinically undruggable target. RAS-like protein (RAL) is a member of the RAS superfamily of small GTPases and is considered to be a potential mediator of oncogenic RAS signaling. In primary MM, we found RAL to be overex-pressed in the vast majority of samples when compared with pre-malignant monoclonal gammopathy of undetermined significance or normal plasma cells. We analyzed the functional effects of RAL abrogation in myeloma cell lines and found that RAL is a critical mediator of survival. RNAi-mediated knockdown of RAL resulted in rapid induction of tumor cell death, an effect which was independent from signaling via mitogen-activated protein kinase, but appears to be partially dependent on Akt activity. Notably, RAL activation was not correlated with the presence of activating RAS muta-tions and remained unaffected by knockdown of oncogenic RAS. Furthermore, transcriptome analysis yielded distinct RNA expression signa-tures after knockdown of either RAS or RAL. Combining RAL depletion with clinically relevant anti-myeloma agents led to enhanced rates of cell death. Our data demonstrate that RAL promotes MM cell survival inde-pendently of oncogenic RAS and, thus, this pathway represents a potential therapeutic target in its own right.