Abstract 4675: Chemoresistant patient-derived xenografts to identify treatment options in breast cancer patients not responding to standard chemotherapy

Abstract

Abstract Resistance to chemotherapy is a major clinical challenge in breast cancer (BC), and patients developing resistance need treatment alternatives. In this project we utilize patient-derived xenografts (PDXs) from triple negative BC (TNBC), as these models better reflect the human tumor complexity and heterogeneity, compared to cell line-based- and transgene animal models. An in-house established orthotopically growing PDX, MAS98.12, has gained resistance to chemotherapy due to prolonged exposure to paclitaxel (MAS98.12-PR), a microtubule-targeting chemotherapeutic agent. As the resistance was obtained in animals, we also have the paclitaxel sensitive equivalent (MAS98.12-PS). By utilizing the pair of sensitive and resistant tumors we can study the corresponding mechanism evolving in patients who initially respond to chemotherapy before resistance and disease progression. This model will aid in identifying key mechanisms of survival in the resistant tumors, and eventually in identifying targets for use as novel therapeutic opportunities in TNBC patients resistant to standard therapy. Finally, we have samples collected early and late after resistance development, allowing us to characterize mechanisms involved in stepwise progression of paclitaxel resistance. We are currently performing molecular profiling to reveal the mechanisms involved in development of resistance. Data from bulk RNAseq, immune profiling of myeloid cells, exome sequencing, secretome profiling and reverse-phase protein array (RPPA) allow for characterizing the isogenic pair of tumors on multiple levels. Preliminary observations include aberrant expression of ABCB1/MDR1, normally involved in translocating drugs across membranes, and previously described as a mechanism involved in pertaining resistance in tumor cells. As multiple attempts to target MDR1 itself has failed, we hypothesize that our PS and PR pair will identify vulnerable/targetable signaling axis in the resistant tumors. Additionally, both PDX models have been assessed for their sensitivity to various chemo-/targeted-drugs and their combinations, revealing alternative means of treating the resistant tumors. Altogether, the molecular profiles and the sensitivity data will give novel knowledge and treatment options for patients failing to respond to standard chemotherapy. Citation Format: Eivind Valen Egeland, Kotryna Seip, Geir Frode Øy, Eleni Skourti, Solveig J Pettersen, Siri Juell, Mads Haugland Haugen, Olav Engebraaten, Lina Prasmickaite, Gunhild M Maelandsmo. Chemoresistant patient-derived xenografts to identify treatment options in breast cancer patients not responding to standard chemotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4675.