Universität zu Köln

Riedel, Richard ORCID: 0000-0002-8883-1188, Ruge, Lea ORCID: 0000-0003-3390-0411, Verheyen, Malte ORCID: 0009-0008-7552-9044, John, Felix ORCID: 0000-0002-0616-3391, Scharpenseel, Heather ORCID: 0000-0001-6322-8350, Nogova, Lucia ORCID: 0000-0002-4502-1812, Michels, Sebastian ORCID: 0000-0003-3164-870X, Fischer, Rieke N. ORCID: 0009-0001-5271-2160, Eisert, Anna, Jakob, Carolin ORCID: 0009-0008-5641-6888, Niesen, Emanuel, Fassunke, Jana ORCID: 0000-0002-8391-5577, Siemanowski-Hrach, Janna ORCID: 0009-0000-8453-5229, Heydt, Carina ORCID: 0000-0003-3184-9579, Bunck, Anne, Siebolts, Udo ORCID: 0009-0000-2336-4737, Merkelbach-Bruse, Sabine ORCID: 0000-0002-0312-5760, Buettner, Reinhard ORCID: 0000-0001-8806-4786, Wolf, Jürgen ORCID: 0000-0002-3869-4736 and Scheffler, Matthias ORCID: 0000-0002-9031-1368 (2026). MET-Driven Resistance to Sotorasib in KRAS G12C–Mutant NSCLC and Response to Combined KRAS and MET Inhibition. JTO Clinical and Research Reports, 7 (3). pp. 1-7. Elsevier. ISSN 26663643

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Abstract

[Artikel-Nr.: 100925] Introduction: KRAS G12C mutations define a molecularly distinct subset of NSCLC for which targeted therapy with sotorasib has exhibited clinical efficacy. However, acquired resistance is inevitable. MET amplification has been described as a putative off-target resistance mechanism, although its clinical relevance remains incompletely understood. Methods: We conducted a retrospective case series of patients with KRAS G12C–mutant NSCLC treated with sotorasib at the University Hospital Cologne, Germany. Patients with available paired pre- and posttreatment bi- opsies were analyzed for resistance mechanisms using routine molecular diagnostics, including MET fluorescence in situ hybridization. Results: Nine patients with paired pre and posttreatment biopsies were identified. High-level MET amplification was detected by fluorescence in situ hybridization in four cases and intermediate-level amplification in one case after progression on sotorasib. Notably, one patient with ac- quired MET amplification achieved a renewed partial response to the combination of sotorasib and tepotinib after progression on sotorasib monotherapy. Conclusion: This study provides real-world evidence that MET amplification is an acquired and potentially targetable resistance mechanism to KRAS G12C inhibition in NSCLC. Our findings support rebiopsy at progression on sotorasib. Further prospective trials are warranted to validate MET amplification as a resistance mechanism and to define optimal therapeutic thresholds for combined KRAS and MET inhibition.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Riedel, Richard UNSPECIFIED https://orcid.org/0000-0002-8883-1188 UNSPECIFIED Ruge, Lea UNSPECIFIED https://orcid.org/0000-0003-3390-0411 UNSPECIFIED Verheyen, Malte UNSPECIFIED https://orcid.org/0009-0008-7552-9044 UNSPECIFIED John, Felix UNSPECIFIED https://orcid.org/0000-0002-0616-3391 UNSPECIFIED Scharpenseel, Heather UNSPECIFIED https://orcid.org/0000-0001-6322-8350 UNSPECIFIED Nogova, Lucia UNSPECIFIED https://orcid.org/0000-0002-4502-1812 UNSPECIFIED Michels, Sebastian UNSPECIFIED https://orcid.org/0000-0003-3164-870X UNSPECIFIED Fischer, Rieke N. UNSPECIFIED https://orcid.org/0009-0001-5271-2160 UNSPECIFIED Eisert, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Jakob, Carolin UNSPECIFIED https://orcid.org/0009-0008-5641-6888 UNSPECIFIED Niesen, Emanuel UNSPECIFIED UNSPECIFIED UNSPECIFIED Fassunke, Jana UNSPECIFIED https://orcid.org/0000-0002-8391-5577 UNSPECIFIED Siemanowski-Hrach, Janna UNSPECIFIED https://orcid.org/0009-0000-8453-5229 UNSPECIFIED Heydt, Carina UNSPECIFIED https://orcid.org/0000-0003-3184-9579 UNSPECIFIED Bunck, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Siebolts, Udo UNSPECIFIED https://orcid.org/0009-0000-2336-4737 UNSPECIFIED Merkelbach-Bruse, Sabine UNSPECIFIED https://orcid.org/0000-0002-0312-5760 UNSPECIFIED Buettner, Reinhard UNSPECIFIED https://orcid.org/0000-0001-8806-4786 UNSPECIFIED Wolf, Jürgen UNSPECIFIED https://orcid.org/0000-0002-3869-4736 UNSPECIFIED Scheffler, Matthias UNSPECIFIED https://orcid.org/0000-0002-9031-1368 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-812681
Identification Number:	10.1016/j.jtocrr.2025.100925
Journal or Publication Title:	JTO Clinical and Research Reports
Volume:	7
Number:	3
Page Range:	pp. 1-7
Number of Pages:	7
Date:	March 2026
Publisher:	Elsevier
ISSN:	26663643
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Innere Medizin > Klinik I für Innere Medizin - Hämatologie und Onkologie Faculty of Medicine > Pathologie und Neuropathologie > Institut für Pathologie Faculty of Medicine > Radiologische Diagnostik > Institut und Poliklinik für Radiologische Diagnostik Faculty of Medicine > Weitere > Centrum für integrierte Onkologie (CIO)
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language NSCLC ; KRAS G12C ; Sotorasib ; MET amplifica- tion ; Tyrosine kinase inhibitor resistance English
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81268