Generation of a predictive melphalan resistance index by drug screen of B-cell cancer cell lines

Background

Recent reports indicate that in vitro drug screens combinedwith gene expression profiles (GEP) of cancer cell lines may generateinformative signatures predicting the clinical outcome of chemotherapy. Inmultiple myeloma (MM) a range of new drugs have been introduced and nowchallenge conventional therapy including high dose melphalan. Consequently,the generation of predictive signatures for response to melphalan may have aclinical impact. The hypothesis is that melphalan screens and GEPs of B-cellcancer cell lines combined with multivariate statistics may providepredictive clinical information.

Materials and Methods

Microarray based GEPs and a melphalan growth inhibition screen of 59 cancercell lines were downloaded from the National Cancer Institute database.Equivalent data were generated for 18 B-cell cancer cell lines. Lineardiscriminant analyses (LDA), sparse partial least squares (SPLS) andpairwise comparisons of cell line data were used to build resistancesignatures from both cell line panels. A melphalan resistance index wasdefined and estimated for each MM patient in a publicly available clinicaldata set and evaluated retrospectively by Cox proportional hazards andKaplan-Meier survival analysis.

Principal Findings

Both cell line panels performed well with respect to internal validation ofthe SPLS approach but only the B-cell panel was able to predict asignificantly higher risk of relapse and death with increasing resistanceindex in the clinical data sets. The most sensitive and resistant celllines, MOLP-2 and RPMI-8226 LR5, respectively, had high leverage, whichsuggests their differentially expressed genes to possess importantpredictive value.

Conclusion

The present study presents a melphalan resistance index generated by analysisof a B-cell panel of cancer cell lines. However, the resistance index needsto be functionally validated and correlated to known MM biomarkers inindependent data sets in order to better understand the mechanism underlyingthe preparedness to melphalan resistance.