AP1-mediated reprogramming of EGFR expression triggers resistance to BLU-667 and LOXO-292 in RET-rearranged tumors
Abstract Background Non-small cell lung cancer (NSCLC) is a significant global health challenge, with 2% of cases fuelled by RET rearrangements. RET inhibitors (RETi) have revolutionized treatment for these patients, but resistance remains an important clinical challenge limiting therapy effectivene...
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BMC
2025-05-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03392-w |
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| author | Daniela Esposito Claudia Maria Ascione Stefania Belli Fabiana Napolitano Alberto Servetto Felice Pepe Umberto Malapelle Antonino Iaccarino Giancarlo Troncone Diletta Barone Emilio Bria Roberto Ferrara Daniele Lorenzini Giuseppe Lo Russo Maria Rosa Ghigna Arianna Marinello Mihaela Aldea Benjamin Besse Luigi Formisano Roberto Bianco |
| author_facet | Daniela Esposito Claudia Maria Ascione Stefania Belli Fabiana Napolitano Alberto Servetto Felice Pepe Umberto Malapelle Antonino Iaccarino Giancarlo Troncone Diletta Barone Emilio Bria Roberto Ferrara Daniele Lorenzini Giuseppe Lo Russo Maria Rosa Ghigna Arianna Marinello Mihaela Aldea Benjamin Besse Luigi Formisano Roberto Bianco |
| author_sort | Daniela Esposito |
| collection | DOAJ |
| description | Abstract Background Non-small cell lung cancer (NSCLC) is a significant global health challenge, with 2% of cases fuelled by RET rearrangements. RET inhibitors (RETi) have revolutionized treatment for these patients, but resistance remains an important clinical challenge limiting therapy effectiveness. This study investigated the mechanisms underlying resistance to RETi. Methods NSCLC cells were exposed to increasing doses of RETi (pralsetinib/BLU-667 and selpercatinib/LOXO-292) to generate resistant cells. RNA-Sequencing analysis identified differentially expressed genes in resistant versus sensitive cells, followed by in vitro and in vivo functional assays to explore novel therapeutic strategies. Additionally, tumor biopsies from RET-rearranged NSCLC patients who exhibited cancer progression on RET inhibitor therapy were analyzed. Results RNA-sequencing analysis revealed the upregulation of the EGFR signaling pathway and hyperactivation of AP1 complex members in resistant cells compared to sensitive cells. Silencing of EGFR and AP1 complex members significantly reversed drug resistance, whereas EGFR overexpression reduced the sensitivity of parental Lc2/AD cells to RET inhibitors. Furthermore, the combination of RET and EGFR inhibitors showed synergistic antitumor activity in vitro and hindered tumor growth in mouse models with resistant cell xenografts. Notably, we observed a significant increase in EGFR expression in tumor biopsies from NSCLC patients treated with RET inhibitors who experienced disease progression, further validating the clinical relevance of our findings. Conclusions This study elucidates EGFR's role in mediating resistance to RET inhibitors in NSCLC patients. These findings offer insights into therapeutic adaptation and explore personalized combinations of RET and EGFR inhibitors for improved clinical outcomes. |
| format | Article |
| id | doaj-art-8e3db07cf4584a8c8c37ed41cec489d6 |
| institution | OA Journals |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-8e3db07cf4584a8c8c37ed41cec489d62025-08-20T01:53:15ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-05-0144111810.1186/s13046-025-03392-wAP1-mediated reprogramming of EGFR expression triggers resistance to BLU-667 and LOXO-292 in RET-rearranged tumorsDaniela Esposito0Claudia Maria Ascione1Stefania Belli2Fabiana Napolitano3Alberto Servetto4Felice Pepe5Umberto Malapelle6Antonino Iaccarino7Giancarlo Troncone8Diletta Barone9Emilio Bria10Roberto Ferrara11Daniele Lorenzini12Giuseppe Lo Russo13Maria Rosa Ghigna14Arianna Marinello15Mihaela Aldea16Benjamin Besse17Luigi Formisano18Roberto Bianco19Department of Clinical Medicine and Surgery, University of Naples “Federico II”Department of Clinical Medicine and Surgery, University of Naples “Federico II”Department of Clinical Medicine and Surgery, University of Naples “Federico II”Department of Clinical Medicine and Surgery, University of Naples “Federico II”Department of Clinical Medicine and Surgery, University of Naples “Federico II”Department of Clinical Medicine and Surgery, University of Naples “Federico II”Department of Public Health, University of Naples Federico IIDepartment of Public Health, University of Naples Federico IIDepartment of Public Health, University of Naples Federico IIUniversity Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, IRCCSUniversity Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, IRCCSUniversity Vita-Salute San RaffaeleDepartment of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale Dei TumoriMedical Oncology Department 1, Fondazione IRCCS Istituto Nazionale Dei TumoriDepartment of Pathology, Gustave RoussyDepartment of Cancer Medicine, Gustave RoussyDepartment of Cancer Medicine, Gustave RoussyDepartment of Cancer Medicine, Gustave RoussyDepartment of Clinical Medicine and Surgery, University of Naples “Federico II”Department of Clinical Medicine and Surgery, University of Naples “Federico II”Abstract Background Non-small cell lung cancer (NSCLC) is a significant global health challenge, with 2% of cases fuelled by RET rearrangements. RET inhibitors (RETi) have revolutionized treatment for these patients, but resistance remains an important clinical challenge limiting therapy effectiveness. This study investigated the mechanisms underlying resistance to RETi. Methods NSCLC cells were exposed to increasing doses of RETi (pralsetinib/BLU-667 and selpercatinib/LOXO-292) to generate resistant cells. RNA-Sequencing analysis identified differentially expressed genes in resistant versus sensitive cells, followed by in vitro and in vivo functional assays to explore novel therapeutic strategies. Additionally, tumor biopsies from RET-rearranged NSCLC patients who exhibited cancer progression on RET inhibitor therapy were analyzed. Results RNA-sequencing analysis revealed the upregulation of the EGFR signaling pathway and hyperactivation of AP1 complex members in resistant cells compared to sensitive cells. Silencing of EGFR and AP1 complex members significantly reversed drug resistance, whereas EGFR overexpression reduced the sensitivity of parental Lc2/AD cells to RET inhibitors. Furthermore, the combination of RET and EGFR inhibitors showed synergistic antitumor activity in vitro and hindered tumor growth in mouse models with resistant cell xenografts. Notably, we observed a significant increase in EGFR expression in tumor biopsies from NSCLC patients treated with RET inhibitors who experienced disease progression, further validating the clinical relevance of our findings. Conclusions This study elucidates EGFR's role in mediating resistance to RET inhibitors in NSCLC patients. These findings offer insights into therapeutic adaptation and explore personalized combinations of RET and EGFR inhibitors for improved clinical outcomes.https://doi.org/10.1186/s13046-025-03392-wNon-small cell lung cancerRETRET inhibitorsEGFRDrug resistanceCombination targeted therapy |
| spellingShingle | Daniela Esposito Claudia Maria Ascione Stefania Belli Fabiana Napolitano Alberto Servetto Felice Pepe Umberto Malapelle Antonino Iaccarino Giancarlo Troncone Diletta Barone Emilio Bria Roberto Ferrara Daniele Lorenzini Giuseppe Lo Russo Maria Rosa Ghigna Arianna Marinello Mihaela Aldea Benjamin Besse Luigi Formisano Roberto Bianco AP1-mediated reprogramming of EGFR expression triggers resistance to BLU-667 and LOXO-292 in RET-rearranged tumors Journal of Experimental & Clinical Cancer Research Non-small cell lung cancer RET RET inhibitors EGFR Drug resistance Combination targeted therapy |
| title | AP1-mediated reprogramming of EGFR expression triggers resistance to BLU-667 and LOXO-292 in RET-rearranged tumors |
| title_full | AP1-mediated reprogramming of EGFR expression triggers resistance to BLU-667 and LOXO-292 in RET-rearranged tumors |
| title_fullStr | AP1-mediated reprogramming of EGFR expression triggers resistance to BLU-667 and LOXO-292 in RET-rearranged tumors |
| title_full_unstemmed | AP1-mediated reprogramming of EGFR expression triggers resistance to BLU-667 and LOXO-292 in RET-rearranged tumors |
| title_short | AP1-mediated reprogramming of EGFR expression triggers resistance to BLU-667 and LOXO-292 in RET-rearranged tumors |
| title_sort | ap1 mediated reprogramming of egfr expression triggers resistance to blu 667 and loxo 292 in ret rearranged tumors |
| topic | Non-small cell lung cancer RET RET inhibitors EGFR Drug resistance Combination targeted therapy |
| url | https://doi.org/10.1186/s13046-025-03392-w |
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