- Email: [email protected]
Clinical response to crizotinib and emergence of resistance in lung adenocarcinoma harboring a MET c-Cbl binding site mutation
Journal Pre-proof Clinical Response to Crizotinib and Emergence of Resistance in Lung Adenocarcinoma Harboring a MET c-Cbl Binding Site Mutation Marcel Wiesweg, Thomas Herold, Martin Metzenmacher, Wilfried E. Eberhardt, Henning Reis, Kaid Darwiche, Clemens Aigner, Martin Stuschke, Ken Herrmann, Felix Nensa, Hans-Ulrich Schildhaus, Martin Schuler
PII:
S0169-5002(19)30745-7
DOI:
https://doi.org/10.1016/j.lungcan.2019.11.020
Reference:
LUNG 6211
To appear in:
Lung Cancer
Received Date:
23 September 2019
Revised Date:
15 November 2019
Accepted Date:
25 November 2019
Please cite this article as: Wiesweg M, Herold T, Metzenmacher M, Eberhardt WE, Reis H, Darwiche K, Aigner C, Stuschke M, Herrmann K, Nensa F, Schildhaus H-Ulrich, Schuler M, Clinical Response to Crizotinib and Emergence of Resistance in Lung Adenocarcinoma Harboring a MET c-Cbl Binding Site Mutation, Lung Cancer (2019), doi: https://doi.org/10.1016/j.lungcan.2019.11.020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
Clinical Response to Crizotinib and Emergence of Resistance in Lung Adenocarcinoma Harboring a MET c-Cbl Binding Site Mutation
Marcel Wiesweg1,3, Thomas Herold2, Martin Metzenmacher1, Wilfried E. Eberhardt1,3, Henning Reis2,
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Kaid Darwiche4, Clemens Aigner5, Martin Stuschke6, Ken Herrmann7, Felix Nensa8, Hans-Ulrich Schildhaus2, Martin Schuler1,3,9 1
Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University
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Duisburg-Essen 2
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Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-
3
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Essen
Division of Thoracic Oncology, West German Lung Center, Ruhrlandklinik - University Hospital Essen,
na
University Duisburg-Essen 4
Department of Pulmonary Medicine, Section of Interventional Pneumology, West German Lung
5
ur
Center, Ruhrlandklinik - University Hospital Essen, University Duisburg-Essen Department of Thoracic Surgery and Endoscopy, West German Lung Center, Ruhrlandklinik -
Jo
University Hospital Essen, University Duisburg-Essen 6
Department of Radiotherapy, West German Cancer Center, University Hospital Essen, University
Duisburg-Essen 7
Department of Nuclear Medicine, West German Cancer Center, University Hospital Essen, University
Duisburg-Essen
8
Institute for Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen,
University Duisburg-Essen 9
German Cancer Consortium (DKTK), Partner Site University Hospital Essen
Corresponding author: Marcel Wiesweg Department of Medical Oncology
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West German Cancer Center University Hospital Essen
-p
Hufelandstrasse 55
re
45122 Essen, Germany
na
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marcel.wiesweg @uk-essen.de
Crizotinib is effective in lung cancer harboring a MET c-Cbl binding site mutation
Jo
ur
Highlights
MET c-Cbl binding site mutations constitute a distinct subtype of exon 14 mutations
Targeted therapy should be offered to patients with cancer driven by such mutations
Abstract Objectives: MET c-Cbl binding site mutations constitute about 2% of MET exon 14 alterations in lung cancer. Preclinical data suggests regarding these mutations as functional analogs of MET exon 14 skipping mutations, but clinical validation is lacking. Results: We report the case of a patient with metastastic lung adenocarcinoma harboring a c-Cbl binding site alteration and demonstrate clinical, radiological and metabolic response to crizotinib with a PFS of 10.6 months. As escape mechanism, a typical MET resistance mutation could be
ro of
identified.
Conclusion: MET c-Cbl binding site mutations should be regarded as a distinct subtype of MET exon 14 alterations. Patients with lung cancer harboring such mutations should be offered targeted
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-p
therapy.
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Introduction
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Key Words: NSCLC, MET mutation, crizotinib, c-Cbl
MET exon 14 skipping mutations are validated oncogenic drivers in lung cancer, which are clinically
Jo
tractable by MET inhibitors. Mechanistically, MET exon 14 encodes the E3 ubiquitin-protein ligase CBL (c-Cbl) binding site, which is essential for regulation by ubiquitination and subsequent degradation of the receptor protein[1]. Point mutations of the Y1021 residue (also known as Y1003), comprising about 2% of MET exon 14 alterations, lead to disruption of the DpYR c-Cbl binding motif. Preclinically they have been characterized as “functional analog” of exon 14 skipping mutations[2,3]. Though the prevalence these rare mutations has been characterized[4], the clinical effectiveness of MET inhibition in this population has not been demonstrated.
Case A 78-year-old man presented with sudden onset of dyspnea. Thoracic CT scan showed bilateral pulmonary embolism, a pulmonary mass in the right upper lobe, pleural nodules and pleural effusion. Pulmonary adenocarcinoma was diagnosed from the malignant effusion. In stage IV disease, amplicon-based NGS diagnostics revealed a MET p.Y1021H (NM_001127500.3: c.3061T>C; NM_000245.3: c.3007T>C, p.Y1003H) c-Cbl binding site mutation. No MET amplification was detected by FISH (gene copy number 1.6).
ro of
In the absence of a clinical study in this molecular entity, single-case approval of treatment with the multikinase inhibitor crizotinib, a known inhibitor of MET, was requested from the patient’s health insurance. Meanwhile, increasing dyspnea due to the pleural effusion required implantation of a
-p
permanent pleural catheter for palliation. The patient presented in reduced condition (ECOG 2) but clinically stable. Crizotinib treatment was approved and initiated 8 weeks after histological diagnosis.
re
Within the first week of therapy, the volume of pleural effusion decreased, and after 3 weeks no
lP
more catheter pleurocenteses were required. In parallel, the patient required no more analgesics and his overall performance improved dramatically. A CT scan obtained after 10 weeks of crizotinib
na
confirmed objective response of the primary tumor and the metastatic pleural nodules. CT scans at 4 and 8 months and an FDG PET-CT scan at 6 months confirmed stable disease and metabolic response (Fig. 1). After 10.6 months of crizotinib, disease progression occurred with multiple new liver
ur
metastases and progressive intrapulmonary lesions. We performed a CT-guided biopsy of one of the
Jo
newly developed liver metastases. Amplicon-based NGS diagnostics (Supplemental Data) revealed emergence of the MET p.D1246N resistance mutation and an FGFR2 mutation (p.S267P) of unclear oncogenic relevance in addition to the activating MET p.Y1021H mutation, which was still present. As no MET kinase inhibitor with known or predicted effectiveness with the p.D1246N mutation was available, chemotherapy with carboplatin and pemetrexed was initiated. The patient achieved a partial remission (treatment ongoing, PFS 3.2 months).
Discussion To the best of our knowledge, we provide the first clinical evidence that MET inhibition by crizotinib is clinically effective in patients with metastatic lung cancer harboring a MET c-Cbl binding site mutation. This confirms that the oncogenic properties of MET mutations rely on the disruption of cCbl binding as key step in maintaining physiological receptor turnover. Our interpretation is supported by clinical, radiological and metabolic response to crizotinib, and the emergence of the typical MET D1246N resistance mutation as escape mechanism. MET D1246N has previously been
ro of
described to occur under crizotinib treatment in lung cancer harboring MET exon 14 skipping mutations[5,6]. Given the preclinical[3], epidemiological[4] and now clinical evidence, we propose to regard MET c-Cbl binding site mutations as a distinct subtype of MET exon 14 alterations. Patients
Jo
ur
na
lP
re
-p
with lung cancer harboring such mutations should be offered targeted therapy.
Potential Conflicts of Interest: Marcel Wiesweg Honoraria: Roche, Boehringer Ingelheim; Research Funding: Bristol-Myers Squibb Martin Metzenmacher Honoraria: Roche, Boehringer Ingelheim Henning Reis Honoraria: Roche, Bristol-Myers Squibb; Research Funding: Bristol-Myers Squibb; Consulting or Advisory Role: Bristol-Myers Squibb
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Wilfried Ernst Erich Eberhardt Honoraria: Eli Lilly, Boehringer Ingelheim, Pfizer, Novartis, Roche, Merck, Bristol-Myers Squibb, Amgen, GlaxoSmithKline, Aestellas, Bayer, Teva, Merck Serono, Daichi Sankyo, Hexal; Consulting or Advisory Role: Eli Lilly, Boehringer Ingelheim, Novartis, Pfizer, Roche, Merck, BristolMyers Squibb, Aestellas, Bayer, Teva, Daichi Sankyo; Research Funding: Eli Lilly (Institutional)
-p
Kaid Darwiche: Consultancy/ Advisory Role: Boehringer Ingelheim, Novartis; Honoraria: Boehringer Ingelheim
Ken Herrmann: Personal fees: Bayer, Amgen, Adacap, Ipsen, BTG, Sirtex, Sofie Biosciences, Siemens Healthineers, GE Healthcare.
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Martin Schuler: Consultancy: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene,
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Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), Lilly, Novartis Honoraria for CME presentations: Alexion, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Lilly, Novartis; Research funding to institution: Boehringer Ingelheim, Bristol Myers-Squibb, Novartis
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Other: Universität Duisburg-Essen (Patents)
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ur
All remaining authors declared no conflicts of interest.
References
[1] A. Drilon, F. Cappuzzo, S.-H.I. Ou, D.R. Camidge, Targeting MET in Lung Cancer: Will Expectations Finally Be MET?, J. Thorac. Oncol. 12 (2017) 15–26. doi:10.1016/j.jtho.2016.10.014. [2] P. Peschard, T.M. Fournier, L. Lamorte, M.A. Naujokas, H. Band, W.Y. Langdon, M. Park, Mutation of the c-Cbl TKB Domain Binding Site on the Met Receptor Tyrosine Kinase Converts It into a Transforming Protein, Mol. Cell. 8 (2001) 995–1004. doi:10.1016/S1097-2765(01)00378-1.
[3] T. Reungwetwattana, Y. Liang, V. Zhu, S.-H.I. Ou, The race to target MET exon 14 skipping alterations in non-small cell lung cancer: The Why, the How, the Who, the Unknown, and the Inevitable, Lung Cancer. 103 (2017) 27–37. doi:10.1016/j.lungcan.2016.11.011. [4] R. Feldman, M. Ellis, J. Swensen, W.M. Korn, Z. Gatalica, MET exon 14 skipping analogs: Rare but potentially clinically actionable., J. Clin. Oncol. 37 (2019) 3141–3141. doi:10.1200/JCO.2019.37.15_suppl.3141. [5] W. Jin, B. Shan, H. Liu, S. Zhou, W. Li, J. Pan, L. Lin, D. Hu, Y. Pan, Acquired Mechanism of
ro of
Crizotinib Resistance in NSCLC with MET Exon 14 Skipping, J. Thorac. Oncol. 14 (2019) e137– e139. doi:10.1016/j.jtho.2019.04.021.
[6] R. Riedel, Carina Heydt, Andreas H. Scheel, Acquired resistance to MET inhibition in MET driven
Jo
ur
na
lP
re
-p
NSCLC., J. Clin. Oncol. 37 (2019). https://abstracts.asco.org/239/AbstView_239_250269.html.
Figure Legends Fig 1: CT and FDG PET CT scans of primary tumor (left column) and pleural nodules (right column) during crizotinib therapy. Minor response at 10 weeks with complete remission of the effusion, then stabile disease. Low metabolic activity at 6.2 months (primary tumors: SUVmax 3.6; pleural nodules:
Jo
ur
na
lP
re
-p
ro of
SUVmax 2.3). Progressive disease with new hepatic lesions at 10.6 months.
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re
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ur
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Fig. 2: Upper part: Sequence of MET exon 14 on DNA and protein level. The DpYR c-Cbl binding motif at codon 1020 – 1022 is marked by a red rectangle. (MET transcript NM_001127500.3, genomic coordinates on hg19). Lower Part: Corresponding mapped NGS reads of the sequence analysis at
Jo
ur
na
lP
re
-p
ro of
initial diagnosis.
PII:
S0169-5002(19)30745-7
DOI:
https://doi.org/10.1016/j.lungcan.2019.11.020
Reference:
LUNG 6211
To appear in:
Lung Cancer
Received Date:
23 September 2019
Revised Date:
15 November 2019
Accepted Date:
25 November 2019
Please cite this article as: Wiesweg M, Herold T, Metzenmacher M, Eberhardt WE, Reis H, Darwiche K, Aigner C, Stuschke M, Herrmann K, Nensa F, Schildhaus H-Ulrich, Schuler M, Clinical Response to Crizotinib and Emergence of Resistance in Lung Adenocarcinoma Harboring a MET c-Cbl Binding Site Mutation, Lung Cancer (2019), doi: https://doi.org/10.1016/j.lungcan.2019.11.020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
Clinical Response to Crizotinib and Emergence of Resistance in Lung Adenocarcinoma Harboring a MET c-Cbl Binding Site Mutation
Marcel Wiesweg1,3, Thomas Herold2, Martin Metzenmacher1, Wilfried E. Eberhardt1,3, Henning Reis2,
ro of
Kaid Darwiche4, Clemens Aigner5, Martin Stuschke6, Ken Herrmann7, Felix Nensa8, Hans-Ulrich Schildhaus2, Martin Schuler1,3,9 1
Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University
-p
Duisburg-Essen 2
re
Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-
3
lP
Essen
Division of Thoracic Oncology, West German Lung Center, Ruhrlandklinik - University Hospital Essen,
na
University Duisburg-Essen 4
Department of Pulmonary Medicine, Section of Interventional Pneumology, West German Lung
5
ur
Center, Ruhrlandklinik - University Hospital Essen, University Duisburg-Essen Department of Thoracic Surgery and Endoscopy, West German Lung Center, Ruhrlandklinik -
Jo
University Hospital Essen, University Duisburg-Essen 6
Department of Radiotherapy, West German Cancer Center, University Hospital Essen, University
Duisburg-Essen 7
Department of Nuclear Medicine, West German Cancer Center, University Hospital Essen, University
Duisburg-Essen
8
Institute for Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen,
University Duisburg-Essen 9
German Cancer Consortium (DKTK), Partner Site University Hospital Essen
Corresponding author: Marcel Wiesweg Department of Medical Oncology
ro of
West German Cancer Center University Hospital Essen
-p
Hufelandstrasse 55
re
45122 Essen, Germany
na
lP
marcel.wiesweg @uk-essen.de
Crizotinib is effective in lung cancer harboring a MET c-Cbl binding site mutation
Jo
ur
Highlights
MET c-Cbl binding site mutations constitute a distinct subtype of exon 14 mutations
Targeted therapy should be offered to patients with cancer driven by such mutations
Abstract Objectives: MET c-Cbl binding site mutations constitute about 2% of MET exon 14 alterations in lung cancer. Preclinical data suggests regarding these mutations as functional analogs of MET exon 14 skipping mutations, but clinical validation is lacking. Results: We report the case of a patient with metastastic lung adenocarcinoma harboring a c-Cbl binding site alteration and demonstrate clinical, radiological and metabolic response to crizotinib with a PFS of 10.6 months. As escape mechanism, a typical MET resistance mutation could be
ro of
identified.
Conclusion: MET c-Cbl binding site mutations should be regarded as a distinct subtype of MET exon 14 alterations. Patients with lung cancer harboring such mutations should be offered targeted
re
-p
therapy.
ur
Introduction
na
lP
Key Words: NSCLC, MET mutation, crizotinib, c-Cbl
MET exon 14 skipping mutations are validated oncogenic drivers in lung cancer, which are clinically
Jo
tractable by MET inhibitors. Mechanistically, MET exon 14 encodes the E3 ubiquitin-protein ligase CBL (c-Cbl) binding site, which is essential for regulation by ubiquitination and subsequent degradation of the receptor protein[1]. Point mutations of the Y1021 residue (also known as Y1003), comprising about 2% of MET exon 14 alterations, lead to disruption of the DpYR c-Cbl binding motif. Preclinically they have been characterized as “functional analog” of exon 14 skipping mutations[2,3]. Though the prevalence these rare mutations has been characterized[4], the clinical effectiveness of MET inhibition in this population has not been demonstrated.
Case A 78-year-old man presented with sudden onset of dyspnea. Thoracic CT scan showed bilateral pulmonary embolism, a pulmonary mass in the right upper lobe, pleural nodules and pleural effusion. Pulmonary adenocarcinoma was diagnosed from the malignant effusion. In stage IV disease, amplicon-based NGS diagnostics revealed a MET p.Y1021H (NM_001127500.3: c.3061T>C; NM_000245.3: c.3007T>C, p.Y1003H) c-Cbl binding site mutation. No MET amplification was detected by FISH (gene copy number 1.6).
ro of
In the absence of a clinical study in this molecular entity, single-case approval of treatment with the multikinase inhibitor crizotinib, a known inhibitor of MET, was requested from the patient’s health insurance. Meanwhile, increasing dyspnea due to the pleural effusion required implantation of a
-p
permanent pleural catheter for palliation. The patient presented in reduced condition (ECOG 2) but clinically stable. Crizotinib treatment was approved and initiated 8 weeks after histological diagnosis.
re
Within the first week of therapy, the volume of pleural effusion decreased, and after 3 weeks no
lP
more catheter pleurocenteses were required. In parallel, the patient required no more analgesics and his overall performance improved dramatically. A CT scan obtained after 10 weeks of crizotinib
na
confirmed objective response of the primary tumor and the metastatic pleural nodules. CT scans at 4 and 8 months and an FDG PET-CT scan at 6 months confirmed stable disease and metabolic response (Fig. 1). After 10.6 months of crizotinib, disease progression occurred with multiple new liver
ur
metastases and progressive intrapulmonary lesions. We performed a CT-guided biopsy of one of the
Jo
newly developed liver metastases. Amplicon-based NGS diagnostics (Supplemental Data) revealed emergence of the MET p.D1246N resistance mutation and an FGFR2 mutation (p.S267P) of unclear oncogenic relevance in addition to the activating MET p.Y1021H mutation, which was still present. As no MET kinase inhibitor with known or predicted effectiveness with the p.D1246N mutation was available, chemotherapy with carboplatin and pemetrexed was initiated. The patient achieved a partial remission (treatment ongoing, PFS 3.2 months).
Discussion To the best of our knowledge, we provide the first clinical evidence that MET inhibition by crizotinib is clinically effective in patients with metastatic lung cancer harboring a MET c-Cbl binding site mutation. This confirms that the oncogenic properties of MET mutations rely on the disruption of cCbl binding as key step in maintaining physiological receptor turnover. Our interpretation is supported by clinical, radiological and metabolic response to crizotinib, and the emergence of the typical MET D1246N resistance mutation as escape mechanism. MET D1246N has previously been
ro of
described to occur under crizotinib treatment in lung cancer harboring MET exon 14 skipping mutations[5,6]. Given the preclinical[3], epidemiological[4] and now clinical evidence, we propose to regard MET c-Cbl binding site mutations as a distinct subtype of MET exon 14 alterations. Patients
Jo
ur
na
lP
re
-p
with lung cancer harboring such mutations should be offered targeted therapy.
Potential Conflicts of Interest: Marcel Wiesweg Honoraria: Roche, Boehringer Ingelheim; Research Funding: Bristol-Myers Squibb Martin Metzenmacher Honoraria: Roche, Boehringer Ingelheim Henning Reis Honoraria: Roche, Bristol-Myers Squibb; Research Funding: Bristol-Myers Squibb; Consulting or Advisory Role: Bristol-Myers Squibb
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Wilfried Ernst Erich Eberhardt Honoraria: Eli Lilly, Boehringer Ingelheim, Pfizer, Novartis, Roche, Merck, Bristol-Myers Squibb, Amgen, GlaxoSmithKline, Aestellas, Bayer, Teva, Merck Serono, Daichi Sankyo, Hexal; Consulting or Advisory Role: Eli Lilly, Boehringer Ingelheim, Novartis, Pfizer, Roche, Merck, BristolMyers Squibb, Aestellas, Bayer, Teva, Daichi Sankyo; Research Funding: Eli Lilly (Institutional)
-p
Kaid Darwiche: Consultancy/ Advisory Role: Boehringer Ingelheim, Novartis; Honoraria: Boehringer Ingelheim
Ken Herrmann: Personal fees: Bayer, Amgen, Adacap, Ipsen, BTG, Sirtex, Sofie Biosciences, Siemens Healthineers, GE Healthcare.
re
Martin Schuler: Consultancy: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene,
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Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), Lilly, Novartis Honoraria for CME presentations: Alexion, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Lilly, Novartis; Research funding to institution: Boehringer Ingelheim, Bristol Myers-Squibb, Novartis
na
Other: Universität Duisburg-Essen (Patents)
Jo
ur
All remaining authors declared no conflicts of interest.
References
[1] A. Drilon, F. Cappuzzo, S.-H.I. Ou, D.R. Camidge, Targeting MET in Lung Cancer: Will Expectations Finally Be MET?, J. Thorac. Oncol. 12 (2017) 15–26. doi:10.1016/j.jtho.2016.10.014. [2] P. Peschard, T.M. Fournier, L. Lamorte, M.A. Naujokas, H. Band, W.Y. Langdon, M. Park, Mutation of the c-Cbl TKB Domain Binding Site on the Met Receptor Tyrosine Kinase Converts It into a Transforming Protein, Mol. Cell. 8 (2001) 995–1004. doi:10.1016/S1097-2765(01)00378-1.
[3] T. Reungwetwattana, Y. Liang, V. Zhu, S.-H.I. Ou, The race to target MET exon 14 skipping alterations in non-small cell lung cancer: The Why, the How, the Who, the Unknown, and the Inevitable, Lung Cancer. 103 (2017) 27–37. doi:10.1016/j.lungcan.2016.11.011. [4] R. Feldman, M. Ellis, J. Swensen, W.M. Korn, Z. Gatalica, MET exon 14 skipping analogs: Rare but potentially clinically actionable., J. Clin. Oncol. 37 (2019) 3141–3141. doi:10.1200/JCO.2019.37.15_suppl.3141. [5] W. Jin, B. Shan, H. Liu, S. Zhou, W. Li, J. Pan, L. Lin, D. Hu, Y. Pan, Acquired Mechanism of
ro of
Crizotinib Resistance in NSCLC with MET Exon 14 Skipping, J. Thorac. Oncol. 14 (2019) e137– e139. doi:10.1016/j.jtho.2019.04.021.
[6] R. Riedel, Carina Heydt, Andreas H. Scheel, Acquired resistance to MET inhibition in MET driven
Jo
ur
na
lP
re
-p
NSCLC., J. Clin. Oncol. 37 (2019). https://abstracts.asco.org/239/AbstView_239_250269.html.
Figure Legends Fig 1: CT and FDG PET CT scans of primary tumor (left column) and pleural nodules (right column) during crizotinib therapy. Minor response at 10 weeks with complete remission of the effusion, then stabile disease. Low metabolic activity at 6.2 months (primary tumors: SUVmax 3.6; pleural nodules:
Jo
ur
na
lP
re
-p
ro of
SUVmax 2.3). Progressive disease with new hepatic lesions at 10.6 months.
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-p
re
lP
na
ur
Jo
Fig. 2: Upper part: Sequence of MET exon 14 on DNA and protein level. The DpYR c-Cbl binding motif at codon 1020 – 1022 is marked by a red rectangle. (MET transcript NM_001127500.3, genomic coordinates on hg19). Lower Part: Corresponding mapped NGS reads of the sequence analysis at
Jo
ur
na
lP
re
-p
ro of
initial diagnosis.