Inhibition of PI3K Class IA Kinases Using GDC-0941 Overcomes Cytoprotection of Multiple Myeloma Cells in the Osteoclastic Bone Marrow Microenvironment Enhancing the Efficacy of Current Clinical Therapeutics

Hugh Kikuchi, Eunice Amofa, Maeve Mcenery, Steve Arthur Schey, Karthik Ramasamy , Farzin Farzaneh , Yolanda Calle

Research output: Contribution to journalArticlepeer-review


Osteoclasts contribute to bone marrow (BM)-mediated drug resistance in multiple myeloma (MM) by providing cytoprotective cues. Additionally, 80% of patients develop osteolytic lesions, which is a major cause of morbidity in MM. Although targeting osteoclast function is critical to improve MM therapies, pre-clinical studies rarely consider overcoming osteoclast-mediated cytoprotection within the selection criteria of drug candidates. We have performed a drug screening and iden-tified PI3K as a key regulator of a signalling node associated with resistance to dexamethasone lenalidomide, pomalidomide, and bortezomib mediated by osteoclasts and BM fibroblastic stro-mal cells, which was blocked by the pan-PI3K Class IA inhibitor GDC-0941. Additionally, GDC-0941 repressed the maturation of osteoclasts derived from MM patients and disrupted the organisation of the F-actin cytoskeleton in sealing zones required for bone degradation, corre-lating with decreased bone resorption by osteoclasts. In vivo, GDC-0941 improved the efficacy of dexamethasone against MM in the syngeneic GFP-5T33/C57-Rawji mouse model. Taken together, our results indicate that GDC-0941 in combination with currently used therapeutic agents could effectively kill MM cells in the presence of the cytoprotective BM microenvironment while in-hibiting bone resorption by osteoclasts. These data support investigating GDC-0941 in combina-tion with currently used therapeutic drugs for MM patients with active bone disease.
Original languageEnglish
Pages (from-to)461-482
Number of pages21
Issue number2
Publication statusPublished - 11 Jan 2023


  • myeloma; tumour microenvironment; co-culture system; dexamethasone; resistance; osteoclasts; high throughput screening

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