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Case Report Open Access

Emergence of KRAS mosaicism with multiple variants during treatment with alectinib in ALK‑positive metastatic non‑small cell lung cancer: A case report

  • Authors:
    • Alizée Simon
    • Gautier Treffel
    • Guillaume Pax
    • Guillaume Gauchotte
    • Marie Husson
    • Idrissia Hanriot
    • Agnès Leroux
    • Jean-Louis Merlin
    • Alexandre Harlé
    • Pauline Gilson
  • View Affiliations / Copyright

    Affiliations: University of Lille, Inserm (French National Institute of Health and Medical Research), Lille Regional University Hospital Center, French National Centre for Scientific Research, Oscar Lambret Center, Joint Research Unit 9020‑CANTHER‑Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000 Lille, France, Department of Pulmonary Medicine, Nancy Regional University Hospital, 54511 Vandœuvre‑lès‑Nancy, France, Department of Biopathology, Lorraine Institute of Cancerology/Nancy Regional University Hospital, 54519 Vandœuvre‑lès‑Nancy, France
    Copyright: © Simon et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 448
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    Published online on: August 5, 2026
       https://doi.org/10.3892/ol.2026.15803
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Abstract

ALK fusions occur in 3‑6% of lung cancers and confer sensitivity to ALK‑tyrosine kinase inhibitors. However, acquired resistance inevitably develops through multiple mechanisms, limiting the durability of the treatment response. The present report describes the case of a 36‑year‑old man with ALK‑rearranged lung adenocarcinoma treated with the second‑generation ALK‑tyrosine kinase inhibitor alectinib. At the time of disease progression, molecular analysis revealed the emergence of a KRAS mosaicism. The present report details the molecular evolution of the tumor, from the initial diagnosis to treatment failure. The current report illustrates a compelling mechanism of resistance to ALK inhibition driven by the synchronous emergence of multiple KRAS variants. While previous case reports have documented an isolated KRAS mutation as a potential resistance mechanism to ALK‑tyrosine kinase inhibitor therapy, to the best of our knowledge, this is the first report describing such extensive KRAS mosaicism upon failure of alectinib treatment. The present report highlights the importance of reevaluating the molecular profile of the cancer at the time of progression to accurately define the resistance pathway and develop rational therapeutic strategies capable of overcoming this resistance.
View Figures

Figure 1

PET scan and bronchoscopy images at
diagnosis. (A) PET scan showing hypermetabolism of the right hilar
mass. 18F-fluorodeoxyglucose-PET/computed tomography
fused transversal images were acquired after 6-h fasting. (B)
Bronchoscopy image showing a mass in the culmen. Biopsies were
obtained through flexible bronchoscopy performed with a
bronchoscope under sedation. The procedure included the
visualization of massive infiltration of the right bronchial tree,
with collection of 10 biopsies for histopathologic examination and
theranostic marker assessment. PET, positron emission
tomography.

Figure 2

ALK, PD-L1 and ROS1
immunohistochemistry images. (A) ALK expression was assessed by
immunohistochemistry. Moderate granular cytoplasm staining was
observed for ALK, with a score of 2+ (magnification, ×200). The
fixative used was 10% buffered formalin. Immunohistochemistry was
performed using the VENTANA Benchmark automated platform (Roche
Tissue Diagnostics). Anti-ALK antibody (clone 5A4; Abcam) was
diluted at 1:100. Antigen retrieval was performed using CC1 for 32
min. The duration of incubation with primary antibody was 1 h.
Detection was performed using OptiView DAB. (B) PD-L1 expression
was assessed by immunohistochemistry. Diffuse membrane staining was
observed for PD-L1 (tumor proportion score, 80%; magnification,
×200). The fixative used was 10% buffered formalin.
Immunohistochemistry was performed using an Agilent OMNIS automated
platform (Agilent Technologies, Inc.). PD-L1 antibody (prediluted;
clone 22C3; Agilent Technologies, Inc.) was used. Antigen retrieval
was performed under low pH conditions for 40 min. The duration of
incubation with primary antibody was 40 min. Detection was
performed using EnVision FLEX+Mouse DAB Enhancer. (C) ROS1
expression was examined using immunohistochemistry. Weak cytoplasm
and membrane staining was observed for ROS1, with a score of 1+
(magnification, ×200). The fixative used was 10% buffered formalin.
Immunohistochemistry was performed using the VENTANA Benchmark
automated platform. Anti-ROS1 antibody (SP384; ready to use) was
used. Antigen retrieval was performed using CC1 for 64 min. The
duration of incubation with primary antibody was 16 min. Detection
was performed using OptiView DAB. ALK, anaplastic lymphoma kinase;
CC1, Cell Conditioning 1; DAB, 3,3′-diaminobenzidine; PD-L1,
programmed death-ligand 1.

Figure 3

Radiological evidence of therapeutic
response and subsequent disease progression. (A) Partial metabolic
response (3 months of alectinib treatment): PET-CT axial slice at
the hilar level showing near-complete disappearance of the
previously described hypermetabolic right hilar mass (compared with
Fig. 1A). (B) Disease progression
(7 months of alectinib treatment): PET-CT axial slice at the level
of the aortic arch revealing multiple new hypermetabolic foci,
including bilateral pulmonary nodules and anterior mediastinal
lymphadenopathy. (C) Further progression (3 months of lorlatinib
treatment): Follow-up CT scan (lung window) at the level of the
aortic arch showing an increase in size of the left hilar mass and
development of multiple bilateral pulmonary nodules. CT, computed
tomography; PET, positron emission tomography.

Figure 4

Phylogenetic tree illustrating the
evolution of genetic mutations in the patient's cancer: Hypotheses
on divergent clonal lineages based on next-generation sequencing
results. The allele frequencies were: i) At diagnosis (second
vertical bar): TP53, 7.2%; EML4::ALK, 97.0%; ii) at first
progression (third vertical bar): KRAS L19F, 2.1%; KRAS G12C, 2.1%;
KRAS G12V, 2.8%; KRAS G12D, 2.8%; KRAS G13C, 2.1%; KRAS Q61H,
23.3%; TP53, 2.9%; and iii) at second progression (fourth vertical
bar): KRAS G13C, 28.7%; TP53, 14.0%; EML4::ALK, 91.0%. The figure
was generated using the ClevRvis package (v.1.8.0; http://github.com/sandmanns/clevRvis)
and R (v.4.3.1; R Core Team; http://www.r-project.org/). ctDNA, circulating tumour
DNA.
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Copy and paste a formatted citation
Spandidos Publications style
Simon A, Treffel G, Pax G, Gauchotte G, Husson M, Hanriot I, Leroux A, Merlin J, Harlé A, Gilson P, Gilson P, et al: Emergence of KRAS mosaicism with multiple variants during treatment with alectinib in ALK‑positive metastatic non‑small cell lung cancer: A case report. Oncol Lett 32: 448, 2026.
APA
Simon, A., Treffel, G., Pax, G., Gauchotte, G., Husson, M., Hanriot, I. ... Gilson, P. (2026). Emergence of KRAS mosaicism with multiple variants during treatment with alectinib in ALK‑positive metastatic non‑small cell lung cancer: A case report. Oncology Letters, 32, 448. https://doi.org/10.3892/ol.2026.15803
MLA
Simon, A., Treffel, G., Pax, G., Gauchotte, G., Husson, M., Hanriot, I., Leroux, A., Merlin, J., Harlé, A., Gilson, P."Emergence of KRAS mosaicism with multiple variants during treatment with alectinib in ALK‑positive metastatic non‑small cell lung cancer: A case report". Oncology Letters 32.4 (2026): 448.
Chicago
Simon, A., Treffel, G., Pax, G., Gauchotte, G., Husson, M., Hanriot, I., Leroux, A., Merlin, J., Harlé, A., Gilson, P."Emergence of KRAS mosaicism with multiple variants during treatment with alectinib in ALK‑positive metastatic non‑small cell lung cancer: A case report". Oncology Letters 32, no. 4 (2026): 448. https://doi.org/10.3892/ol.2026.15803
Copy and paste a formatted citation
x
Spandidos Publications style
Simon A, Treffel G, Pax G, Gauchotte G, Husson M, Hanriot I, Leroux A, Merlin J, Harlé A, Gilson P, Gilson P, et al: Emergence of KRAS mosaicism with multiple variants during treatment with alectinib in ALK‑positive metastatic non‑small cell lung cancer: A case report. Oncol Lett 32: 448, 2026.
APA
Simon, A., Treffel, G., Pax, G., Gauchotte, G., Husson, M., Hanriot, I. ... Gilson, P. (2026). Emergence of KRAS mosaicism with multiple variants during treatment with alectinib in ALK‑positive metastatic non‑small cell lung cancer: A case report. Oncology Letters, 32, 448. https://doi.org/10.3892/ol.2026.15803
MLA
Simon, A., Treffel, G., Pax, G., Gauchotte, G., Husson, M., Hanriot, I., Leroux, A., Merlin, J., Harlé, A., Gilson, P."Emergence of KRAS mosaicism with multiple variants during treatment with alectinib in ALK‑positive metastatic non‑small cell lung cancer: A case report". Oncology Letters 32.4 (2026): 448.
Chicago
Simon, A., Treffel, G., Pax, G., Gauchotte, G., Husson, M., Hanriot, I., Leroux, A., Merlin, J., Harlé, A., Gilson, P."Emergence of KRAS mosaicism with multiple variants during treatment with alectinib in ALK‑positive metastatic non‑small cell lung cancer: A case report". Oncology Letters 32, no. 4 (2026): 448. https://doi.org/10.3892/ol.2026.15803
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