Early tolerance and late persistence as alternative drug responses in cancer

Simona Punzi (), Davide Cittaro, Guido Gatti, Gemma Crupi, Oronza A. Botrugno, Antonino Alex Cartalemi, Alon Gutfreund, Caterina Oneto, Valentina Giansanti, Chiara Battistini, Giovanni Santacatterina, Lucrezia Patruno, Ilaria Villanti, Martina Palumbo, Daniel J. Laverty, Francesca Giannese, Alex Graudenzi, Giulio Caravagna, Marco Antoniotti, Zachary Nagel, Ugo Cavallaro, Luisa Lanfrancone, Timothy A. Yap, Giulio Draetta, Nathalie Balaban and Giovanni Tonon ()
Additional contact information
Simona Punzi: IRCCS San Raffaele Scientific Institute
Davide Cittaro: IRCCS San Raffaele Scientific Institute
Guido Gatti: IRCCS San Raffaele Scientific Institute
Gemma Crupi: IRCCS San Raffaele Scientific Institute
Oronza A. Botrugno: IRCCS San Raffaele Scientific Institute
Antonino Alex Cartalemi: IRCCS San Raffaele Scientific Institute
Alon Gutfreund: The Hebrew University of Jerusalem
Caterina Oneto: IRCCS San Raffaele Scientific Institute
Valentina Giansanti: IRCCS San Raffaele Scientific Institute
Chiara Battistini: European Institute of Oncology IRCSS
Giovanni Santacatterina: University of Trieste
Lucrezia Patruno: Systems and Communication of the University of Milan-Bicocca
Ilaria Villanti: Università Vita-Salute San Raffaele
Martina Palumbo: IRCCS San Raffaele Scientific Institute
Daniel J. Laverty: Harvard Chan School of Public Health
Francesca Giannese: IRCCS San Raffaele Scientific Institute
Alex Graudenzi: Systems and Communication of the University of Milan-Bicocca
Giulio Caravagna: University of Trieste
Marco Antoniotti: Systems and Communication of the University of Milan-Bicocca
Zachary Nagel: Harvard Chan School of Public Health
Ugo Cavallaro: European Institute of Oncology IRCSS
Luisa Lanfrancone: European Institute of Oncology IRCCS
Timothy A. Yap: The University of Texas MD Anderson Cancer Center
Giulio Draetta: The University of Texas MD Anderson Cancer Center Houston
Nathalie Balaban: The Hebrew University of Jerusalem
Giovanni Tonon: IRCCS San Raffaele Scientific Institute

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-54728-7

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