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

SIMPLE SUMMARY: The activation of osteoclasts occurs in up to 80% of myeloma patients. Osteoclasts promote myeloma resistance to therapeutic treatments and the formation of bone lytic lesions, resulting in bone pain and fractures in patients. However, the role of osteoclasts in drug resistance is generally overseen when performing preclinical screenings to identify new therapeutics for multiple myeloma. We propose in our study a new methodology, scalable to high throughput for the analysis of drug efficacy to better predict efficacy in myeloma patients that develop bone disease. We have identified GDC-0941 as a drug candidate that, used in combination treatments, could enhance the efficacy of currently used therapeutic drugs for myeloma by overcoming resistance mediated by osteoclasts, as well as bone marrow mesenchymal/fibroblastic stromal cells. Our work supports exploring GDC-0941 in combination with current clinical drugs for myeloma patients with active bone disease. ABSTRACT: 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 identified PI3K as a key regulator of a signalling node associated with resistance to dexamethasone lenalidomide, pomalidomide, and bortezomib mediated by osteoclasts and BM fibroblastic stromal 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, correlating 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 inhibiting bone resorption by osteoclasts. These data support investigating GDC-0941 in combination with currently used therapeutic drugs for MM patients with active bone disease.