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.
Highlights
A combination of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) is the current gold standard therapy for multiple myeloma (MM) with response rates in ~90% of newly diagnosed patients, deep complete remission is only achieved in ~50%, and most patients relapse, due to innate and acquired drug resistance[1,2,3,4,5,6,7,8]
For the non-Hodgkin’s lymphoma cell lines (NHLCLs), mantle and T-cell lymphoma subtypes were maintained in RPMI-1640 supplemented with 10% FBS and 1% pen/strep, while diffuse large B-cell lymphoma (DLBCL) subtypes were maintained in IMDM media supplemented with 20% human serum and 1% pen/strep
Creation of a phase 0 drug screening platform A “direct to drug” strategy for drug sensitivity profiling was developed with a panel of 76 pre-screened small molecules comprising Food and Drug Administration (FDA)-approved, cancer clinical trial, or biologically relevant emerging therapeutics
Summary
A combination of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) is the current gold standard therapy for multiple myeloma (MM) with response rates in ~90% of newly diagnosed patients, deep complete remission is only achieved in ~50%, and most patients relapse, due to innate and acquired drug resistance[1,2,3,4,5,6,7,8]. Is to understand the mechanisms of Because MM evolves secondary to acquired genetic events[18], efforts toward individualizing treatments have, until now, focused on sequencing strategies[19,20,21]. Such early efforts have, failed to stimulate an era of precision medicine since actionable mutations are rare, subclonal, and lack matched therapeutics. Even when actionable mutations are present and the appropriate drug is utilized (e.g., treating BRAFV600E), clinical responses have been incomplete and transient[22,23]
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