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

doi:10.3390/cancers15020462

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 journal › Article › peer-review

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 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 language	English
Pages (from-to)	461-482
Number of pages	21
Journal	Cancers
Volume	15
Issue number	2
DOIs	https://doi.org/10.3390/cancers15020462
Publication status	Published - 11 Jan 2023

Keywords

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

Access to Document

10.3390/cancers15020462

https://www.mdpi.com/2072-6694/15/2/462/html

Cite this

Kikuchi, H., Amofa, E., Mcenery, M., Schey, S. A., Ramasamy , K., Farzaneh , F., & Calle, Y. (2023). 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. Cancers, 15(2), 461-482. https://doi.org/10.3390/cancers15020462

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title = "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",

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 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.",

keywords = "myeloma; tumour microenvironment; co-culture system; dexamethasone; resistance; osteoclasts; high throughput screening",

author = "Hugh Kikuchi and Eunice Amofa and Maeve Mcenery and Schey, {Steve Arthur} and Karthik Ramasamy and Farzin Farzaneh and Yolanda Calle",

year = "2023",

month = jan,

day = "11",

doi = "10.3390/cancers15020462",

language = "English",

volume = "15",

pages = "461--482",

journal = "Cancers",

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Kikuchi, H, Amofa, E, Mcenery, M, Schey, SA, Ramasamy , K, Farzaneh , F & Calle, Y 2023, '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', Cancers, vol. 15, no. 2, pp. 461-482. https://doi.org/10.3390/cancers15020462

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. / Kikuchi, Hugh; Amofa, Eunice; Mcenery, Maeve et al.
In: Cancers, Vol. 15, No. 2, 11.01.2023, p. 461-482.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

AU - Kikuchi, Hugh

AU - Amofa, Eunice

AU - Mcenery, Maeve

AU - Schey, Steve Arthur

AU - Ramasamy , Karthik

AU - Farzaneh , Farzin

AU - Calle, Yolanda

PY - 2023/1/11

Y1 - 2023/1/11

N2 - 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.

AB - 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.

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

U2 - 10.3390/cancers15020462

DO - 10.3390/cancers15020462

M3 - Article

SN - 2072-6694

VL - 15

SP - 461

EP - 482

JO - Cancers

JF - Cancers

IS - 2

ER -