Exploiting Induced Vulnerability To Overcome PARPi Resistance and Clonal Heterogeneity in BRCA Mutant Triple-Negative Inflammatory Breast Cancer

Authors

David J H Shih
Mei-Kuang Chen
Jun Yin
Daniel J McGrail
Hui Dai
Rongbin Wei
Jing Zhang
Wenjin Jim Zheng
Kim-Anh Do
Liuqing Yang
Mien-Chie Hung
Shiaw-Yih Lin

Publication Date

1-1-2022

Journal

American Journal of Cancer Research

Abstract

Acquired resistance and clonal heterogeneity are critical challenges in cancer treatment, and the lack of effective computational tools hampers the discovery of new treatments to overcome resistance. Using high-throughput transcriptomic databases of compound perturbation profiles, we have developed a bioinformatic strategy for identifying candidate drugs to overcome resistance with combinatorial therapy. We devised this strategy during an investigation into the acquired resistance against PARP inhibitors (PARPi) in a triple-negative inflammatory breast cancer cell line. In this study, we derived multiple PARPi-resistant clones and characterized their transcriptomic adaptations compared to the parental clone. The transcriptomes of the resistant clones showed substantial heterogeneity, highlighting the importance of characterizing multiple clones from the same tumour. Surprisingly, we found that these transcriptomic changes may not actually confer PARPi resistance, but they may nevertheless induce a shared secondary vulnerability. By modeling our data in relation to transcriptomic perturbation profiles of compounds, we uncovered deficiencies in Ras signaling that resulted from transcriptional adaptation to long-term PARPi treatment across multiple resistant clones. Due to these induced deficiencies, we predicted that the resistant clones would be sensitive to pharmacological reinforcement of PARPi-induced transcriptional adaptation. We then experimentally validated this predicted vulnerability that is shared by multiple resistant clones. Our results thus provide a promising paradigm for integrating transcriptomic data with compound perturbation profiles in order to identify drugs that can exploit an induced vulnerability and overcome therapeutic resistance, thus providing another strategy towards precision oncology.

Keywords

PARP inhibitor resistance, triple-negative inflammatory breast cancer, clonal heterogeneity, transcriptomics, pharmacogenomics

PMID

35141022

PMCID

PMC8822293

PubMedCentral® Posted Date

1-15-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes