دورية أكاديمية
AXL and Error-Prone DNA Replication Confer Drug Resistance and Offer Strategies to Treat EGFR-Mutant Lung Cancer
| العنوان: | AXL and Error-Prone DNA Replication Confer Drug Resistance and Offer Strategies to Treat EGFR-Mutant Lung Cancer |
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| المؤلفون: | Noronha, Ashish, Belugali Nataraj, Nishanth, Lee, Joo Sang, Zhitomirsky, Benny, Oren, Yaara, Oster, Sara, Lindzen, Moshit, Mukherjee, Saptaparna, Will, Rainer, Ghosh, Soma, Simoni-Nieves, Arturo, Verma, Aakanksha, Chatterjee, Rishita, Borgoni, Simone, Robinson, Welles, Sinha, Sanju, Brandis, Alexander, Kerr, D Lucas, Wu, Wei, Sekar, Arunachalam, Giri, Suvendu, Chung, Youngmin, Drago-Garcia, Diana, Danysh, Brian P, Lauriola, Mattia, Fiorentino, Michelangelo, Ardizzoni, Andrea, Oren, Moshe, Blakely, Collin M, Ezike, Jideofor, Wiemann, Stefan, Parida, Laxmi, Bivona, Trever G, Aqeilan, Rami I, Brugge, Joan S, Regev, Aviv, Getz, Gad, Ruppin, Eytan, Yarden, Yosef |
| المساهمون: | Noronha, Ashish, Belugali Nataraj, Nishanth, Lee, Joo Sang, Zhitomirsky, Benny, Oren, Yaara, Oster, Sara, Lindzen, Moshit, Mukherjee, Saptaparna, Will, Rainer, Ghosh, Soma, Simoni-Nieves, Arturo, Verma, Aakanksha, Chatterjee, Rishita, Borgoni, Simone, Robinson, Welle, Sinha, Sanju, Brandis, Alexander, Kerr, D Luca, Wu, Wei, Sekar, Arunachalam, Giri, Suvendu, Chung, Youngmin, Drago-Garcia, Diana, Danysh, Brian P, Lauriola, Mattia, Fiorentino, Michelangelo, Ardizzoni, Andrea, Oren, Moshe, Blakely, Collin M, Ezike, Jideofor, Wiemann, Stefan, Parida, Laxmi, Bivona, Trever G, Aqeilan, Rami I, Brugge, Joan S, Regev, Aviv, Getz, Gad, Ruppin, Eytan, Yarden, Yosef |
| سنة النشر: | 2022 |
| المجموعة: | IRIS Università degli Studi di Bologna (CRIS - Current Research Information System) |
| مصطلحات موضوعية: | Human, ErbB Receptor, Receptor Protein-Tyrosine Kinase, Proto-Oncogene Protein, Protein Kinase Inhibitor, Drug Resistance, Neoplasm, Mutation, Cell Line, Tumor, Anti-Bacterial Agent, DNA Replication, DNA-Binding Protein, Ubiquitin-Protein Ligase, Lung Neoplasms |
| الوصف: | Anticancer therapies have been limited by the emergence of mutations and other adaptations. In bacteria, antibiotics activate the SOS response, which mobilizes error-prone factors that allow for continuous replication at the cost of mutagenesis. We investigated whether the treatment of lung cancer with EGFR inhibitors (EGFRi) similarly engages hypermutators. In cycling drug-tolerant persister (DTP) cells and in EGFRi-treated patients presenting residual disease, we observed upregulation of GAS6, whereas ablation of GAS6's receptor, AXL, eradicated resistance. Reciprocally, AXL overexpression enhanced DTP survival and accelerated the emergence of T790M, an EGFR mutation typical to resistant cells. Mechanistically, AXL induces low-fidelity DNA polymerases and activates their organizer, RAD18, by promoting neddylation. Metabolomics uncovered another hypermutator, AXL-driven activation of MYC, and increased purine synthesis that is unbalanced by pyrimidines. Aligning anti-AXL combination treatments with the transition from DTPs to resistant cells cured patient-derived xenografts. Hence, similar to bacteria, tumors tolerate therapy by engaging pharmacologically targetable endogenous mutators. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | ELETTRONICO |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/35895872; info:eu-repo/semantics/altIdentifier/wos/WOS:000892504400001; volume:12; issue:11; firstpage:2666; lastpage:2683; numberofpages:18; journal:CANCER DISCOVERY; info:eu-repo/grantAgreement/EC/H2020/740469; https://hdl.handle.net/11585/899390Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85141659800; https://aacrjournals.org/cancerdiscovery/article/12/11/2666/710003/AXL-and-Error-Prone-DNA-Replication-Confer-DrugTest |
| DOI: | 10.1158/2159-8290.CD-22-0111 |
| الإتاحة: | https://doi.org/10.1158/2159-8290.CD-22-0111Test https://hdl.handle.net/11585/899390Test https://aacrjournals.org/cancerdiscovery/article/12/11/2666/710003/AXL-and-Error-Prone-DNA-Replication-Confer-DrugTest |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.F2C8062A |
| قاعدة البيانات: | BASE |
| DOI: | 10.1158/2159-8290.CD-22-0111 |
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