Pseudo-temporal dynamics of chemoresistant triple negative breast cancer cells reveal EGFR/HER2 inhibition as synthetic lethal during mid-neoadjuvant chemotherapy

Pseudo-temporal dynamics of chemoresistant triple negative breast cancer cells reveal EGFR/HER2 inhibition as synthetic lethal during mid-neoadjuvant chemotherapy

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Summary: In the absence of targetable hormonal axes, chemoresistance for triple-negative breast cancer (TNBC) often compromises patient outcomes.To investigate the underlying tumor color touch 7/97 dynamics, we performed trajectory analysis on the single-nuclei RNA-seq (snRNA-seq) of chemoresistant tumor clones during neoadjuvant chemotherapy (NAC).It revealed a common tumor trajectory across multiple patients with HER2-like expansions during NAC.

Genome-wide CRISPR-Cas9 knock-out on mammary epithelial cells revealed chemosensitivity-promoting knock-outs were up-regulated along the tumor trajectory.Furthermore, we derived a consensus gene signature of TNBC chemoresistance by comparing the trajectory transcriptome with chemoresistant transcriptomes from TNBC cell lines and poor prognosis patient samples to predict FDA-approved drugs, including afatinib (pan-HER inhibitor), targeting the consensus signature.We validated the synergistic efficacy of afatinib and paclitaxel in chemoresistant iphone 13 pro max price winnipeg TNBC cells and confirmed pharmacological suppression of the consensus signature.

The study provides a dynamic model of chemoresistant tumor transcriptome, and computational framework for pharmacological intervention.