Identification Of Genetic And Metabolic Impairments To Improve Chemotherapeutic Efficacy.

Abstract Genetic polymorphisms associated with drug metabolism can significantly impair chemotherapeutic efficacy. Some African American women have poor treatment response to taxane-based chemotherapy drugs, which are widely used to treat breast cancer (BCa). Our study sought to identify gene-metabolite interactions to determine how selected polymorphisms impact treatment-relevant metabolic pathways that may contribute to poor response. This approach will enable more precise treatment based on genetically-defined metabolic drug-response as well as the consideration of ethnicity which can also play a role in disparate cancer outcomes. We treated a panel of four BCa cell lines derived from tumors taken from African American or Caucasian women with paclitaxel, at LD50 ≈ 100 ng/mL, determined by MTT assay across all lines. Cell pellets were collected for three replicate experiments for treated versus untreated conditions and UPLC high resolution mass spectrometry untargeted metabolomics was performed to identify significantly perturbed metabolic pathways that differentiate response to paclitaxel treatment. We observed differentiation between the four cell lines based on the specific metabolites that separated treated versus control/line using supervised multivariate analysis. Further, three endogenous pathways (Benzoate degradation via CoA ligation, Electron transport chain and Nucleotide sugar metabolism) were significantly perturbed (p<0.05) only in the Caucasian-derived line (HCC1937) compared to the three African American-derived lines (HCC70, HCC1500 and HCC1806). Additional selective pathway perturbations in response to paclitaxel included Arachidonic acid metabolism, shown only in HCC1806 cells, as well as O-Glycan biosynthesis and Vitamin D3 metabolism, found only in HCC1500 cells. We further investigated single nucleotide polymorphisms (SNPs) in 28 candidate genes involved in paclitaxel or other chemo drug metabolism, in these cells plus four additional BCa cell lines (BT-474, MCF-7, MDA-MB-231 and MDA-MB-468). Preliminary findings for three SNPs rs2231142 (in ABCG2, ATP binding cassette subfamily G member 2), rs1800440 (in CYP1B1, Cytochrome P450 family 1 subfamily B member 1) and rs1695 (in GSTP1, Glutathione S-transferase pi 1) demonstrated genetic differences across the lines, based on either ethnicity of derivation (four African American-derived versus four Caucasian-derived), hormone receptor positivity (ER+/PR+/HER2+ versus ER+/PR+/HER2- versus ER-/PR-/HER2+) or triple-negative subtype (ER-/PR-/HER2-) classification. We are currently determining the targetable interactions between these SNPs and others with allelic differences, and metabolic responses to paclitaxel, which will enable us to test strategies for by-passing these impairments to improve treatment efficacy. Citation Format: Herman L. Freeman, Yuan-yuan Li, Susan L. McRitchie, Wimal W. Pathmasiri, Susan J. Sumner, Baba B. Mass, Brea C. Nance, Saroja Voruganti, Delisha Antionette Stewart. Identification of genetic and metabolic impairments to improve chemotherapeutic efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2355.