“Direct to Drug” screening as a precision medicine tool in multiple myeloma

Cecilia Bonolo de Campos, Nathalie Meurice, Joachim L. Petit, Alysia N. Polito, Yuan Xiao Zhu, Panwen Wang, Laura A. Bruins, Xuewei Wang, Ilsel D. Lopez Armenta, Susie A. Darvish, Greg J. Ahmann, Kimberly J. Henderson, Shulan Tian, Jonas J. Kruse, William M. Stewart, Jeremy T. Larsen, Craig B. Reeder, David Dingli, Prashant Kapoor, Shaji K. KumarRafael Fonseca, P. Leif Bergsagel, Esteban Braggio, A. Keith Stewart

Research output: Contribution to journalArticle

Abstract

Seventy-six FDA-approved oncology drugs and emerging therapeutics were evaluated in 25 multiple myeloma (MM) and 15 non-Hodgkin’s lymphoma cell lines and in 113 primary MM samples. Ex vivo drug sensitivities were mined for associations with clinical phenotype, cytogenetic, genetic mutation, and transcriptional profiles. In primary MM samples, proteasome inhibitors, dinaciclib, selinexor, venetoclax, auranofin, and histone deacetylating agents had the broadest cytotoxicity. Of interest, newly diagnosed patient samples were globally less sensitive especially to bromodomain inhibitors, inhibitors of receptor tyrosine kinases or non-receptor kinases, and DNA synthesis inhibitors. Clustering demonstrated six broad groupings of drug sensitivity linked with genomic biomarkers and clinical outcomes. For example, our findings mimic clinical observations of increased venetoclax responsiveness in t(11;14) patients but also identify an increased sensitivity profile in untreated patients, standard genetic risk, low plasma cell S-Phase, and in the absence of Gain(1q) and t(4;14). In contrast, increased ex vivo responsiveness to selinexor was associated with biomarkers of poor prognosis and later relapse patients. This “direct to drug” screening resource, paired with functional genomics, has the potential to successfully direct appropriate individualized therapeutic approaches in MM and to enrich clinical trials for likely responders.

Original languageEnglish (US)
Article number54
JournalBlood cancer journal
Volume10
Issue number5
DOIs
StatePublished - May 1 2020

ASJC Scopus subject areas

  • Hematology
  • Oncology

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    Bonolo de Campos, C., Meurice, N., Petit, J. L., Polito, A. N., Zhu, Y. X., Wang, P., Bruins, L. A., Wang, X., Lopez Armenta, I. D., Darvish, S. A., Ahmann, G. J., Henderson, K. J., Tian, S., Kruse, J. J., Stewart, W. M., Larsen, J. T., Reeder, C. B., Dingli, D., Kapoor, P., ... Stewart, A. K. (2020). “Direct to Drug” screening as a precision medicine tool in multiple myeloma. Blood cancer journal, 10(5), [54]. https://doi.org/10.1038/s41408-020-0320-7