Multiple Myeloma Signaling

RESEARCHSECTION WATCH

Signaling

Major finding: Phosphorylation of Concept: GPCR kinase-induced phos- Impact: GPCR drug design strategies GPCRs on distinct sites dictates phorylation patterns confer specificity must consider specific barcodes and β-arrestin conformation and function. and complexity to GPCR signaling. corresponding β-arrestin states.

b-ARRESTIN ACTIVITY IS DIRECTED BY A PHOSPHORYLATION BARCODE β-Arrestins are adaptor proteins that are key regulators of displays quantitatively distinct readouts dependent on the G protein-coupled receptors (GPCR), which constitute the proximity of the β-arrestin2 N- and C-termini. The BRET as- largest signaling family in the genome. Following GPCR ac- say indicated that knockdown of GRK2 and GRK6 produces tivation, phosphorylation of GPCR intracellular loops or cy- 2 distinct β-arrestin2 conformations. Proteomic analysis of

toplasmic tails by GPCR kinases (GRK) recruits β-arrestins, β2AR phosphorylation sites following GRK2 or GRK6 deple- which uncouple the G protein from the receptor and induce tion revealed that these GRKs phosphorylate distinct regions receptor desensitization and internalization. Once bound to and sites, suggesting a general mechanism for specific induc- a GPCR, β-arrestins can serve as scaffolds for other proteins, tion of β-arrestin conformations and downstream signaling and have been linked to oncogenic signaling pathways and events by individual GRKs. Because of the large degree of het- metastatic cell behavior. Because GRKs differentially regulate erogeneity among GPCRs and the existence of other GRKs GPCR function, Nobles and colleagues hypothesized that in- and β-arrestins, future studies will be necessary to characterize dividual GRKs phosphorylate distinct GPCR sites, constitut- the effects of GRK-mediated phosphorylation on all aspects ing a “barcode” which would impact the conformation and of β-arrestin function. However, because GPCRs are attractive downstream function of β-arrestins. Indeed, the authors show drug targets, barcodes for desirable cellular conditions and that GRK2 and GRK6 differentially regulate β-arrestin2- β-arrestin states can be exploited in future drug screens. ≠ dependent internalization and ERK signaling downstream of

the β2-adrenergic G-coupled receptor (β2AR). To demonstrate Nobles KN , Xiao K , Ahn S , Shukla AK , Lam CM , Rajagopal S , that these differences were due to distinct conformations of et al. Distinct phosphorylation sites on the β2-adrenergic receptor β-arrestin, the authors utilized a β-arrestin2 bioluminescence establish a barcode that encodes differential functions of β-arrestin. resonance energy transfer (BRET)-based biosensor, which Sci Signal 2011 ; 4 : ra51 .

Multiple Myeloma

Major finding: Lenalidomide is a sub- Approach: Phase I clinical trial evalu- Future direction: Development of reg- strate of P-glycoprotein. ated lenalidomide and CCI-779 in pa- imens including lenalidomide should tients with relapsed MM. consider that it is a P-gp substrate.

LENALIDOMIDE AND CCI-779 TREATMENT FOR RELAPSED MULTIPLE MYELOMA Multiple myeloma (MM) is an incurable is a substrate of P-glycoprotein (P-gp), an hematologic malignancy of plasma cells in ATP-dependent drug efflux pump encoded the bone marrow. Lenalidomide, an effec- by the ABCB1 gene. The authors therefore tive immunomodulatory and tumoricidal hypothesized that an interaction was occur- agent, is a derivative of thalidomide and a ring during drug transport. In vitro studies standard treatment for initial and relapsed confirmed that lenalidomide is also a P-gp MM. Preclinical models have demonstrated substrate and its efflux from cells is inhib- that the PI3K/Akt/mTOR pathway plays a ited by CCI-779. Taken together, the findings role in MM pathogenesis, suggesting that are an example of how clinical observations inhibition of this pathway in combination can reciprocally drive basic science research. with lenalidomide may provide additional The molecular mechanism underlying the therapeutic benefit. CCI-779 (temsirolimus), which targets drug interaction may explain both the increased systemic mTOR, showed single agent efficacy in a phase II study concentrations of lenalidomide and related toxicities seen of MM, and CCI-779 combined with lenalidomide dem- in the trial and informs the future development of thera- onstrated synergy in vitro. These observations prompted peutic regimens that include lenalidomide. ≠ Hofmeister and colleagues to conduct a phase I clinical trial of lenalidomide in combination with CCI-779 in pa- Hofmeister CC , Yang X , Pichiorri F , Chen P , Rozewski DM , tients with relapsed MM. Although the study established Johnson AJ , et al. Phase I trial of lenalidomide and CCI-779 in pa- the maximum-tolerated dose of the combination, adverse tients with relapsed multiple myeloma: evidence for lenalidomide- events were more frequent than expected and pharmacoki- CCI-779 interaction via P-glycoprotein. J Clin Oncol. 2011 Aug 8 . netic analysis suggested a drug-drug interaction. CCI-779 [Epub ahead of print]

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7953_ResearchWatch_pp282-284.indd 283 8/30/11 3:16 PM β-Arrestin Activity Is Directed by a Phosphorylation Barcode

Cancer Discovery 2011;1:283.

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