Abstract
BackgroundGynecologic malignancy is one of the leading causes of mortality in female adults worldwide. Comprehensive genomic analysis has revealed a list of molecular aberrations that are essential to tumorigenesis, progression, and metastasis of gynecologic tumors. However, targeting such alterations has frequently led to treatment failures due to underlying genomic complexity and simultaneous activation of various tumor cell survival pathway molecules. A compilation of molecular characterization of tumors with pharmacological drug response is the next step toward clinical application of patient-tailored treatment regimens.ResultsToward this goal, we establish a library of 139 gynecologic tumors including epithelial ovarian cancers (EOCs), cervical, endometrial tumors, and uterine sarcomas that are genomically and/or pharmacologically annotated and explore dynamic pharmacogenomic associations against 37 molecularly targeted drugs. We discover lineage-specific drug sensitivities based on subcategorization of gynecologic tumors and identify TP53 mutation as a molecular determinant that elicits therapeutic response to poly (ADP-Ribose) polymerase (PARP) inhibitor. We further identify transcriptome expression of inhibitor of DNA biding 2 (ID2) as a potential predictive biomarker for treatment response to olaparib.ConclusionsTogether, our results demonstrate the potential utility of rapid drug screening combined with genomic profiling for precision treatment of gynecologic cancers.
Highlights
Gynecologic malignancy is one of the leading causes of mortality in female adults worldwide
Somatic mutations of CTNNB1 were predominantly observed in endometrial cancers (EC) compared with other gynecologic cancer types (P = 3.153 × 10−03, Fisher’s exact test) [22], indicating that targeting of Wnt/ß-catenin pathway could potentially provide clinical benefits for EC patients [27, 28]
Through lineage-specific drug sensitivity analysis (Additional file 5: Table S4), we discovered that EGFR inhibitors including erlotinib, dacomitinib, and ibrutinib, a BTK inhibitor that was previously shown to have profound anti-EGFR activities [19, 35], were highly sensitive in epithelial ovarian cancers (EOCs) (P = 2.91 × 10−02, P = 3.59 × 10−02, and P = 2.24 × 10−02, Fig. 2 Lineage-specific drug sensitivity among gynecologic tumors. a Volcano plot representation of gynecologic tumor type-specific drug response, with fold-change drug comparison (x-axis) and its significance (y-axis)
Summary
Gynecologic malignancy is one of the leading causes of mortality in female adults worldwide. Large-scale genomic characterizations of ovarian, uterine, and cervical cancers have been profiled by The Cancer Genome Atlas (TCGA) Research Network [20,21,22,23], clinical application potential of molecular targeted therapy remains obscure. Toward this goal, we have established a library of short-term cultured PDC models and performed comprehensive analyses of pharmacogenomic interactions to identify potential molecular determinants that could guide personalized treatment in gynecologic tumors
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