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Case Reports
. 2025 May 30;14(5):1862-1869.
doi: 10.21037/tlcr-2024-1149. Epub 2025 May 28.

Visceral crisis in a patient with non-small cell lung cancer and ROS1::SDC4 fusion: intrinsic resistance to entrectinib via L2026M mutation-a case report

Vaneza Avila Rodriguez  1   2 , Nicolle Wagner-Gutiérrez  3 , Jairo Andrés Zuluaga León  1   2 , Leonardo Rojas  1   2 , Lucia Viola  1   2 , Stella Isabel Martínez Jaramillo  1   2 , Carlos Andrés Carvajal Fierro  1   2 , Alejandro Ruiz-Patiño  1   2   3   4 , Oscar Arrieta  5   6 , Luis Corrales  6   7 , Claudio Martin  6   8 , Andrés F Cardona  1   2   6
Affiliations
Case Reports

Visceral crisis in a patient with non-small cell lung cancer and ROS1::SDC4 fusion: intrinsic resistance to entrectinib via L2026M mutation-a case report

Vaneza Avila Rodriguez et al. Transl Lung Cancer Res. .

Abstract

Background: ROS1 rearrangements are identified in approximately 1-2% of non-small cell lung cancer (NSCLC) cases, predominantly in younger, non-smoking patients. Targeted therapies such as entrectinib, a second-generation ROS1 tyrosine kinase inhibitor (TKI), have demonstrated efficacy, particularly in managing brain metastases. However, intrinsic and acquired resistance mechanisms remain poorly understood, limiting long-term treatment success.

Case description: We report a unique case of early entrectinib resistance due to a gatekeeper mutation in the ROS1 kinase domain, underscoring the importance of molecular profiling in optimizing therapeutic strategies. We report a case of a 50-year-old male, a non-smoker, who was diagnosed with ROS1-rearranged NSCLC harboring an ROS1::SDC4 fusion. First-line treatment with entrectinib was initiated, resulting in an initial partial response. However, rapid disease progression was observed within a few months. Retrospective molecular analysis identified the L2026M mutation in the ROS1 kinase domain, a known gatekeeper mutation that reduces TKI binding affinity and enhances tumor cell survival. This case highlights the clinical impact of resistance mutations in ROS1-positive NSCLC and underscores the critical role of comprehensive molecular profiling in guiding treatment decisions.

Conclusions: The emergence of the L2026M mutation suggests a need for next-generation TKIs and combination strategies to overcome resistance. Future studies should explore novel inhibitors targeting ROS1 resistance pathways to improve outcomes in this subset of NSCLC patients.

Keywords: L2026M; ROS1::SDC4 fusion; Resistance mechanism; case report; entrectinib.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1149/coif). J.A.Z.L. reports the payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Merck Sharp & Dome, Boehringer Ingelheim, Bristol-Myers Squibb; payment for expert testimony from AstraZeneca, Bristol-Myers Squibb, Pfizer; support for attending meetings and/or travel from Addium Pharma, AstraZeneca, Merck Sharp & Dome, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Novartis, Eli Lilly; and receipt of equipment, materials, drugs, medical writing, gifts or other services from AstraZeneca, Pfizer, Roche. S.I.M.J. reports the payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astrazeneca, Medtronic, Johnson & Johnson, MSD. C.A.C.F. reports payment or honoraria as the Astrazeneca speaker. A.R.P. reports the payment for presentation honoraria from Astra Zeneca, Amgen, Bayer, Bristol Myers Squibb, Böhringer Ingelheim, Glaxo Smith Kline, Johnson and Johnson, Merck Sharpe and Dohme, Pfizer, and support for attending meetings and/or travel from Johnson and Johnson. L.C. reports the payment for presentations from Roche. A.F.C. reports the grants from Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Foundation Medicine, Roche Diagnostics, Termo Fisher, Broad Institute, Amgen, Flatiron Health, Teva Pharma, Rochem Biocare, Bayer, INQBox and The Foundation for Clinical and Applied Cancer Research – FICMAC; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from EISAI, Merck Serono, Jannsen Pharmaceutical, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Novartis, Celldex Therapeutics, Foundation Medicine, Eli Lilly, Guardant Health, Illumina, and Foundation for Clinical and Applied Cancer Research-FICMAC; payment for expert testimony from Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Novartis, Foundation Medicine, Guardant Health, Illumina, and Foundation for Clinical and Applied Cancer Research-FICMAC; support for attending meetings and/or travel from Merck Serono, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Novartis, Celldex Therapeutics, Foundation Medicine, Eli Lilly, and Foundation for Clinical and Applied Cancer Research-FICMAC; participation on a Data Safety Monitoring Board or Advisory Board of Roche, Merck Sharp & Dohme; and receipt of equipment, materials, drugs, medical writing, gifts or other services from Roche, Roche diagnostics, Rochem Biocare. The other authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Timeline of clinical evolution and response to treatment. Created in biorender. ECOG, Eastern Cooperative Oncology Group performance status; IMRT, intensity-modulated radiation therapy; PET-CT, positron emission tomography-computed tomography; SRS, stereotactic radiosurgery.
Figure 2
Figure 2
ROS1 pathway and resistance mechanisms. (A) ROS1 pathway and intrinsic resistance mechanisms. The ROS1 receptor’s domain structure, predicted through homology with other proteins, includes nine fibronectin type III motifs, three β-propeller (YWTD repeat) domains, a single transmembrane domain, and an intracellular tyrosine KD. In mice, NELL2 interacts with ROS1 in the epididymis, promoting homodimerization or oligomerization, which activates the KD, leading to autophosphorylation and ROS1 signaling. ROS1 catalytic activity triggers key signaling pathways, including MAPK: promotes cellular proliferation and survival; PI3K-AKT-mTOR: regulates cell growth and survival; JAK-STAT3: drives gene expression changes related to oncogenesis; VAV3-RHO: facilitates cytoskeletal remodeling and enhances cell migration. Autophosphorylation occurs at tyrosine residues in the intracellular domain. Phosphatases, such as SHP2 (PTPN6), activate RTK signaling, while SHP1 (PTPN11) inactivates it. These processes lead to RHO-dependent cytoskeletal remodeling, promoting cell survival, proliferation, migration, and invasiveness—key characteristics of oncogenesis. Resistance mutations occur in the KD, particularly at SF residues and the GK site, disrupting TKI binding and contributing to resistance. (B) ROS1 pathway and extrinsic resistance mechanisms. Extrinsic resistance mechanisms involve mutations or amplifications that activate alternative signaling pathways, bypassing ROS1 inhibition. Key alterations include PI3KCA mutations, which drive cell growth and survival; BRAFV600F mutations, activating the MAPK pathway; MET amplification, promoting bypass signaling; and EGFR amplification, further enhancing proliferative signals. Created in biorender: https://app.biorender.com/illustrations/673144e58d3d734c6c1fa794. GK, gatekeeper; KD, kinase domain; MAPK, RAS-RAF-MEK-ERK; NELL2, neural epidermal growth factor-like 2; RTK, receptor tyrosine kinase; SF, solvent-front.
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