title: Microenvironmental influence on pre-clinical activity of polo-like kinase inhibition in multiple myeloma: implications for clinical translation.
abstract: Polo-like kinases (PLKs) play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM). We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50<40 nM) and rapid (commitment to cell death <24 hrs) in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mouse model. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional in vitro and in vivo preclinical assays don't take into account how interactions between MM cells and the bone microenvironment can potentially confer drug resistance. To probe this question, we performed tumor cell compartment-specific bioluminescence imaging assays to compare the preclinical anti-MM activity of BI 2536 in vitro in the presence vs. absence of stromal cells or osteoclasts. We observed that the presence of these bone marrow non-malignant cells led to decreased anti-MM activity of BI 2536. We further validated these results in an orthotopic in vivo mouse model of diffuse MM bone lesions where tumor cells interact with non-malignant cells of the bone microenvironment. We again observed that BI 2536 had decreased activity in this in vivo model of tumor-bone microenvironment interactions highlighting that, despite BI 2536's promising activity in conventional assays, its lack of activity in microenvironmental models raises concerns for its clinical development for MM. More broadly, preclinical drug testing in the absence of relevant tumor microenvironment interactions may overestimate potential clinical activity, thus explaining at least in part the gap between preclinical vs. clinical efficacy in MM and other cancers.
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: McMillin
authors.forename: Jake
authors.initials: J
authors.lastname: Delmore
authors.forename: Joseph
authors.initials: J
authors.lastname: Negri
authors.forename: Melissa
authors.initials: M
authors.lastname: Ooi
authors.forename: Steffen
authors.initials: S
authors.lastname: Klippel
authors.forename: Chandrasekhar V
authors.initials: CV
authors.lastname: Miduturu
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
mesh_terms: D015153:Blotting, Western; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology*; D017154:Stromal Cells / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D053148:Caspase 3; D018797:Cell Cycle Proteins; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C518477:BI 2536