Early tolerance and late persistence as alternative drug responses in cancer

Bacteria withstand antibiotic treatment through three alternative mechanisms: resistance, persistence or tolerance. While resistance and persistence have been described, whether drug-induced tolerance exists in cancer cells remains largely unknown. Here, we show that human cancer cells elicit a tolerant response when exposed to commonly used chemotherapy regimens, propelled by the pervasive activation of autophagy, leading to the comprehensive activation of DNA damage repair pathways. After prolonged drug exposure, such tolerant responses morph into persistence, whereby the increased DNA damage repair is entirely reversed. The central regulator of mitophagy PINK1 drives this reduction in DNA repair via the cytoplasmic relocalization of the cell identity master HNF4A, thus hampering HNF4A transcriptional activation of DNA repair genes. We conclude that exposing cancer cells to relevant standard-of-care antitumour therapies induces a pervasive drug-induced tolerant response that might be broadly exploited to increase the impact of first-line, adjuvant treatments and debulking in advanced cancers.

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Publication Details

Journal
Nature Communications
Published
2025-02-03
DOI
https://doi.org/10.1038/s41467-024-54728-7
Citations
5
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
4.03

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article

Early tolerance and late persistence as alternative drug responses in cancer

Valentina Giansanti, Nathalie Q. Balaban, Guido Gatti, Daniel J. Laverty et al.
5 citations
Nature Communications
Single-cell and spatial transcriptomics
4.03
article

Early tolerance and late persistence as alternative drug responses in cancer

Valentina Giansanti, Nathalie Q. Balaban, Guido Gatti, Daniel J. Laverty, Simona Punzi, Giovanni Santacatterina, Caterina Oneto, Luisa Lanfrancone, Giulio Caravagna, Giulio Draetta, Marco Antoniotti, Davide Cittaro, Chiara Battistini, Giovanni Tonon, Lucrezia Patruno, Alex Graudenzi, Francesca Giannese, Oronza A. Botrugno, Timothy Anthony Yap, Ugo Cavallaro, Zachary D. Nagel, Giancarlo Crupi, Martina Palumbo, Alon Gutfreund, Ilaria Villanti, Antonino Alex Cartalemi
article en
5 citations

Abstract

Bacteria withstand antibiotic treatment through three alternative mechanisms: resistance, persistence or tolerance. While resistance and persistence have been described, whether drug-induced tolerance exists in cancer cells remains largely unknown. Here, we show that human cancer cells elicit a tolerant response when exposed to commonly used chemotherapy regimens, propelled by the pervasive activation of autophagy, leading to the comprehensive activation of DNA damage repair pathways. After prolonged drug exposure, such tolerant responses morph into persistence, whereby the increased DNA damage repair is entirely reversed. The central regulator of mitophagy PINK1 drives this reduction in DNA repair via the cytoplasmic relocalization of the cell identity master HNF4A, thus hampering HNF4A transcriptional activation of DNA repair genes. We conclude that exposing cancer cells to relevant standard-of-care antitumour therapies induces a pervasive drug-induced tolerant response that might be broadly exploited to increase the impact of first-line, adjuvant treatments and debulking in advanced cancers.

Nature CommunicationsVol. 16(1)
The University of Texas MD Anderson Cancer Center (US), Harvard University (US), University of Trieste (IT), Vita-Salute San Raffaele University (IT), Hebrew University of Jerusalem (IL), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), European Institute of Oncology (IT), University of Milano-Bicocca (IT)
Cancer Research UK, Associazione Italiana per la Ricerca sul Cancro, Fondazione Italiana per la Ricerca sul Cancro, Agenzia Italiana del Farmaco, Ministero della Salute
Good health and well-being
Openalex Percentile: Top 7%
Single-cell and spatial transcriptomics
4.03
DOIOpen Access PDFOpenAlex
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