Patient-Derived Xenografts of Triple-Negative Breast Cancer Enable Deconvolution and Prediction of Chemotherapy Responses

Abstract

Combination chemotherapy remains essential for clinical management of triple-negative breast cancer (TNBC). Consequently, responses to individual agents cannot be easily delineated at the single patient level, even though some patients might not require all drugs in the combination. Herein, we conduct multi-omic analyses of orthotopic TNBC patient-derived xenografts (PDXs) treated with single agent carboplatin, docetaxel, or the combination. Combination responses were usually no better than the best single agent, with enhanced response in only ~13% of PDX, and apparent antagonism in a comparable percentage. Single-omic comparisons showed largely non-overlapping results between genes associated with single agent and combination treatments that could be validated in independent patient cohorts. Multi-omic analyses of PDXs identified agent-specific biomarkers/biomarker combinations, nominating high Cytokeratin-5 (KRT5) as a general marker of responsiveness. Notably, integrating proteomic with transcriptomic data improved predictive modeling of pathologic complete response to combination chemotherapy. PDXs refractory to all treatments were enriched for signatures of dysregulated mitochondrial function. Targeting this process indirectly with HDAC inhibition plus chemotherapy in vivo overcomes resistance in a subset of PDX. These results suggest possible resistance mechanisms and therapeutic strategies in TNBC to overcome chemoresistance, and potentially allow optimization of chemotherapeutic regimens.

Competing Interest Statement

M.T.L is a Founder of, and an uncompensated Limited Partner in, StemMed Ltd., and an uncompensated Manager in StemMed Holdings L.L.C., its General Partner. M.T.L. is also a Founder of, and equity stake holder in, Tvardi Therapeutics Inc.. L.E.D. is a compensated employee of StemMed Ltd. Selected BCM PDX models described herein are exclusively licensed to StemMed Ltd. resulting in tangible property royalties to M.T.L. and L.E.D. Washington University in St. Louis has licensed selected PDX to Envigo which results in tangible property royalties to S.L. He also received research funding from Pfizer, Takeda Oncology, Zenopharm, independent of this project. S.L has received license fees from Envigo and also received research funding from Pfizer, Takeda Oncology, Zenopharm, outside of this project. M.J.E. is founder of Progendis, Inc and received consulting fees from Abbvie, Sermonix, Pfizer, AstraZeneca, Celgene, NanoString, Puma, Veracyte, Eli Lilly and Novartis, and is an equity stockholder and Board Director member of BioClassifier. M.J.E. is an inventor on a patent for the Breast Cancer PAM50-based assay, Prosigna, which is marketed by Veracyte. M.J.E. also receives royalties from Washington University in St. Louis when the WHIM PDX models are licensed to for-profit companies. M.F.R. received consulting fees from Pfizer, Novartis, AstraZeneca, and Gilead. C.K.O. is a stockholder of GeneTex. S.D. received consulting free from Taiho Oncology. F.M-B has advisory roles in Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis; and received consulting fee from AbbVie, Aduro BioTech, Alkermes, AstraZeneca, Daiichi Sankyo, DebioPharm, Ecor1 Capital, eFFECTOR Therapeutics, F. Hoffman-La Roche, GT Apeiron, Genentech, Harbinger Health, IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer, Protai Bio, Samsung Bioepis, Seattle Genetics, Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks, European Organization for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO). B.Z. received consulting fee from AstraZeneca. G.V.E. receives sponsored research funding from Chimerix, Inc, and experimental research compounds from Chimerix, Inc and the Lead Discovery Center of Germany. M.A. received research funding from AstraZeneca. University of Utah may license the HCI PDX models described herein to for-profit companies, which may result in tangible property royalties to A.L.W. and/or B.E.W. A.L.W. has received research funding from AbbVie. All other authors have nothing to disclose.