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A Novel PRKAR1A::MET Fusion Dramatic Response to Crizotinib in a Patient with Unresectable Lung Cancer

  • Author Footnotes
    § These authors equally contributed to this publication.
    Yang Yang
    Footnotes
    § These authors equally contributed to this publication.
    Affiliations
    Department of Respiratory Diseases, Harbin Medical University Cancer Hospital, Heilongjiang Province, Harbin, China
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  • Author Footnotes
    § These authors equally contributed to this publication.
    Yanxiang Zhang
    Footnotes
    § These authors equally contributed to this publication.
    Affiliations
    Department of Translational Medicine, Genetron Health (Beijing) Co. Ltd., Beijing, China
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  • Dandan Zhao
    Affiliations
    Department of Translational Medicine, Genetron Health (Beijing) Co. Ltd., Beijing, China
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  • Author Footnotes
    # Tonghui Ma and Xiaoli Li are corresponding authors.
    Xiaoli Li
    Correspondence
    Address for correspondence: Xiaoli Li, MD, PhD, Department of Respiratory Diseases, Harbin Medical University Cancer Hospital, Haping Road No. 150, Harbin 150081, China
    Footnotes
    # Tonghui Ma and Xiaoli Li are corresponding authors.
    Affiliations
    Department of Respiratory Diseases, Harbin Medical University Cancer Hospital, Heilongjiang Province, Harbin, China
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  • Author Footnotes
    # Tonghui Ma and Xiaoli Li are corresponding authors.
    Tonghui Ma
    Correspondence
    Address for correspondence: Tonghui Ma, PhD, Department of Translational Medicine, Genetron Health (Beijing) Co. Ltd., NO. 8 Science Park Road, Changping District, Beijing 102206, China
    Footnotes
    # Tonghui Ma and Xiaoli Li are corresponding authors.
    Affiliations
    Department of Translational Medicine, Genetron Health (Beijing) Co. Ltd., Beijing, China
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  • Author Footnotes
    § These authors equally contributed to this publication.
    # Tonghui Ma and Xiaoli Li are corresponding authors.
Open AccessPublished:October 13, 2022DOI:https://doi.org/10.1016/j.cllc.2022.10.001

      Clinical Practice Points

      • This report demonstrated a significant clinical benefit from first-line treatment of crizotinib in a patient with unresectable lung cancer with novel PRKAR1A::MET gene fusion.
      • After disease progress resulted from discontinued therapy, the patient still achieved clinical benefit from second-line monotherapy of crizotinib.
      • This finding provided insight to perform the clinical trials to assess the efficacy and rationale of first-line or second line treatment to patients with unresectable lung cancer carrying MET fusion.

      Keywords

      Abbreviations:

      ALK (Anaplastic Lymphoma Kinase and), CT (Computed Tomography), ECOG (Eastern Cooperative Oncology Group), FDA (Food and Drug Administration), HLA-DRB1 (Human Leukocyte Antigen-DRB1), KIF5B (Kinesin Family 5B), MET (Mesenchymal Epithelial Transition Factor), MSI (Microsatellite Instability), NCCN (National Comprehensive Cancer Network), NGS (Next-generation Sequencing), NSCLC (Non-small Cell Lung Cancer), PRKAR1A (cAMP-dependent Protein Kinase Type I-alpha Regulatory Subunit), ROS1 (Reactive Oxygen Species proto-oncogene 1 (ROS1)), STARD3NL (Steroidogenic Acute Regulatory Protein-related Lipid Transfer Domain-3 N-terminal Like), TMB (Tumor Mutational Burden)

      Introduction

      Genomic alterations in c-Mesenchymal–Epithelial Transition Factor (c-MET, hereafter referred to as MET) promote tumor cell proliferation and metastasis in many kinds of human malignancies.
      • Guo R
      • Luo J
      • Chang J
      • et al.
      MET-dependent solid tumours - molecular diagnosis and targeted therapy.
      MET amplifications and MET exon 14 skipping mutations are well studied, which accounts for 1% to 5% and 3% to 4% of non-small cell lung cancers (NSCLC).
      • Tong JH
      • Yeung SF
      • Chan AW
      • et al.
      MET Amplification and Exon 14 splice site mutation define unique molecular subgroups of non-small cell lung carcinoma with poor prognosis.
      Recent studies also revealed crizotinib effectively inhibited genomic alterations of MET including gene amplification and exon 14 skipping mutations in patients with NSCLC.
      • Guo R
      • Luo J
      • Chang J
      • et al.
      MET-dependent solid tumours - molecular diagnosis and targeted therapy.
      • Awad MM.
      Impaired c-met receptor degradation mediated by MET Exon 14 mutations in non-small-cell lung cancer.
      Therefore, the latest version of NCCN Guidelines recommended crizotinib as category 2A level for a first-line therapy or subsequent therapy option for MET exon 14 mutations or MET high-level amplification in advanced NSCLC. However, MET gene fusions are rare oncogenic driver alterations and poorly implicated in NSCLC, and the standard TKI treatment has not been determined for these patients. In our study, we reported the case of NSCLC harboring a novel PRKAR1A::MET gene fusion dramatic response to crizotinib.

      Case Report

      A 67-year-old female patient (never-smoker) presented in the hospital with a complaint of intermittent left-sided chest pain that had lasted for 3 months. She also complained of mild productive cough and expectoration over 3-month. Her family history was unremarkable except that her brother had died of gastric cancer. Chest CT scans revealed left lower lobe mass and bilateral enlarged mediastinal/hilar lymph nodes, as well as accompanied by emphysema and bilateral pulmonary inflammation. In April 2020, CT-guided needle aspiration (18G) of the lung lesion was performed, and pathologically diagnosed with poorly differentiated lung adenocarcinoma (Figure 1A). Finally, the patient was diagnosed with unresectable lung adenocarcinoma (stage IIIA: cT1 N2 M0) according to the eighth edition of TNM staging.
      Figure 1
      Figure 1Pathological findings.
      (A) Hematoxylin and eosin staining shows poorly differentiated lung adenocarcinoma. (B) Immunohistochemical staining displays positive signal for MET in tumor cells. Scale bar: 50 μm.
      We recommended regimens of chemotherapy or chemoradiotherapy, while the patient and her family members wished to avoid the cytotoxic chemotherapy or the combination regimens of chemoradiotherapy. To explore other actionable treatments, the patient was referred for genetic testing by DNA-based NGS (Onco PanScan, Genetron Health, Co. Ltd., Beijing, China). DNA extraction, sequencing library construction, sequencing and bioinformatics analysis were carried out in Genetron Health, Co. Ltd. Both tumor tissues and matched white blood cells were analyzed by the Onco PanScan which was DNA-based NGS product targeting 825 cancer related genes and provided companion diagnostic results including genetic variations for guiding targeted therapies and TMB and MSI status for immunotherapy. For analyses of genetic variations, non-synonymous single nucleotide variations (SNVs), insertions/deletion (indel) variants, copy number variations (CNVs), gene fusions were included. The tumor mutation burden (TMB) was determined by the total numbers of non-synonymous SNVs and indel variants per magabase of coding regions. MSI status was calculated with 309 microsatellite sites of the Onco PanScan examined.
      The genetic testing indicated the tumor tissue harboring somatic variations of ABL2, ACTL6B, BCORL1, CTNNB1, DROSHA, ITGB2, KEAP1, MLH1, MYOD1, NEGR1, RBM10, SIX1, and STAT5A. None of pathogenic germline variation was detected in matched white blood cells. At that time, certain genetic variations in 8 genes are recommended to test for advanced NSCLC patients according to the NCCN Guidelines, including EGFR (exon 19 deletion, p.L858R, p.T790M, and exon 20 insertion), ALK, ROS1 and RET rearrangements, BRAF (p.V600E), KRAS (p.G12X), ERBB2 mutations, MET amplifications and exon 14 skipping.
      • Ettinger D
      • Wood D
      • Aggarwal C
      • et al.
      NCCN Guidelines insights: non-small cell lung cancer, version 1.2020.
      However, these genes variations were negative in the tumor tissue from the patient. The genetic testing also revealed a low TMB value (7.04 mutations per megabase) and microsatellite stability. These results suggested that the patient could not benefit from targeted therapy or immunotherapy. However, we found a genomic structure variation in the tumor sample of the patient, a novel PRKAR1A::MET gene fusion (allele frequency: 8.2%) with breakpoints in introns 5 and 14, respectively (Figure 2A).
      Figure 2
      Figure 2PRKAR1A::MET gene fusion.
      (A) DNA sequencing reads are aligned by genomics Viewer software. (B) RNA sequencing reads are indicated by genomics Viewer software. (C) Schematic representation of PRKAR1A::MET gene fusion and potential functional fusion protein. Abbreviation: RDD = regulatory dimerization domain; TKR = tyrosine kinase receptor.
      To confirm MET gene fusion at transcriptional level, total RNA was extracted from resection sample and subjected to RNA-based NGS (FusionCapture, Genetron Health, Co. Ltd., Beijing, China). The result showed exons 1 to 5 of PRKAR1A fused to exons 15 to 21 of MET (Figure 2B). The PRKAR1A::MET gene fusion retained the complete regulatory dimerization domain of PRKAR1A and the intact kinase domain of MET (Figure 2C). To evaluate c-MET protein expression, immunohistochemistry assay was performed. A strong positive signal of c-MET was observed in Figure 1B, suggesting c-MET was accumulated in the tumor cells of the patient. These results supported that the novel PRKAR1A::MET gene fusion which might be a rare oncogenic driver as potential targets for targeted therapies. Therefore, we speculated our patient might benefit from crizotinib treatment and the patient and her family members consented to conduct crizotinib monotherapy.
      The patient initiated to take crizotinib (250 mg twice a day) on July 1, 2020, and stopped taking crizotinib due to the adverse events, including nausea, vomiting and anorexia on the drug on July 29, 2020. Compared to CT image in the baseline (Figure 3A), dramatic tumor shrinkage was observed at 29 days after first-line crizotinib treatment (Figure 3B). Although we communicated with the patient and her family members regarding the management and health education, she still wished to stop taking crizotinib. Thereafter, the patient did not receive any antitumor therapy. On October 12, 2020, the patient presented in our hospital for follow-up, CT scans displayed left lower lobe mass (Figure 3C) was disease progressed at 75 days after discontinued crizotinib therapy. The patient still refused any antitumor therapy until a severe pain in the chest in March, 2021. Therefore, we recommended crizotinib treatment and additional 2 stomach drugs of metoclopramide and omeprazole, and the patient consented the therapeutic regimen and restarted to take crizotinib on April 01, 2021. She had no adverse events after the dose of crizotinib was halved (250 mg once a day). On November 12, 2021, CT scans revealed nearly complete response (Figure 3D) at 226 days after second-line crizotinib treatment. At last follow-up, a continued nearly complete response was achieved at 274 days after crizotinib treatment (Figure 3E), and the patient had a good physical condition. The timeline of relevant clinical data was illustrated in Figure 4, including diagnosis, interventions and disease process during course of clinical care.
      Figure 3
      Figure 3The course of crizotinib treatment.
      (A) CT scan image before crizotinib treatment. (B) CT scan image at 29 days after first-line monotherapy of crizotinib. (C) CT scan image at 75 days after discontinuing treatment. (D) and (E) CT scan image at 226 days and 274 days after second-line monotherapy of crizotinib, respectively. Red arrows represent tumor mass.
      Figure 4
      Figure 4The timeline of diagnosis and treatment history. Crizo, crizotinib; LADC, lung adenocarcinoma; MET = c-mesenchymal–epithelial transition factor; PD = progressive disease; PR = partial response; nCR = nearly complete response.

      Discussion

      MET gene fusions were reported rarely due to the rare event and distinct diagnostic challenges in the clinic.
      • Guo R
      • Luo J
      • Chang J
      • et al.
      MET-dependent solid tumours - molecular diagnosis and targeted therapy.
      In the present study, we identified a novel PRKAR1A::MET gene fusion retained the complete regulatory dimerization domain of PRKAR1A and the intact kinase domain of MET in a patient with NSCLC. Several cases carrying MET fusion with intact kinase domain have been reported in NSCLC, including CAV1-MET, CD47-MET, HLA-DRB1-MET, KIF5B-MET, SPECC1L-MET, and STARD3NL-MET.
      • Davies KD
      • Ng TL
      • Estrada-Bernal A
      • et al.
      Dramatic response to crizotinib in a patient with lung cancer positive for an HLA-DRB1-MET gene fusion.
      • Blanc-Durand F
      • Alameddine R
      • Iafrate AJ
      • et al.
      Tepotinib efficacy in a patient with non-small cell lung cancer with brain metastasis harboring an HLA-DRB1-MET gene fusion.
      • Cho JH
      • Ku BM
      • Sun JM
      • et al.
      KIF5B-MET Gene rearrangement with robust antitumor activity in response to crizotinib in lung adenocarcinoma.
      • Plenker D
      • Bertrand M
      • de Langen AJ
      • et al.
      Structural alterations of MET trigger response to MET kinase inhibition in lung adenocarcinoma patients.
      • Pan Y
      • Zhang Y
      • Ye T
      • et al.
      Detection of novel NRG1, EGFR, and MET fusions in lung adenocarcinomas in the chinese population.
      • Liu J
      • Li X
      • Peng J.
      A Novel CAV1-MET fusion in SCLC transformation responds to crizotinib and osimertinib treatment.
      • Nelson AW
      • Schrock AB
      • Pavlick DC
      • et al.
      Novel SPECC1L-MET fusion detected in circulating tumor DNA in a patient with lung adenocarcinoma following treatment with erlotinib and osimertinib.
      It was predicted that KIF5B-MET and STARD3NL-MET fusions activated in MET activation via dimerization mechanism, while other fusion proteins (CAV1-MET, CD47-MET, KIF5B-MET, and SPECC1L-MET) might result in the constitute kinase activity of MET with unknown mechanism.
      • Guo R
      • Luo J
      • Chang J
      • et al.
      MET-dependent solid tumours - molecular diagnosis and targeted therapy.
      In our study, the mechanism of the novel PRKAR1A::MET fusion is uncertain, although a strong signal of MET accumulation was observed in the tumor tissue from the patient (Figure 1B). It is suggested that PRKAR1A fused to N-terminal of MET can lead to constitute MET activation probably owing to the dimerization of MET via dimerization domain of PRKAR1A. It is also supposed that this fusion resulting in exclusion of MET exon 14 may mimic MET exon 14 mutations, which might stabilize MET due to the lack of the ubiquitination motif in exon 14.
      • Awad MM.
      Impaired c-met receptor degradation mediated by MET Exon 14 mutations in non-small-cell lung cancer.
      It is necessary to perform more studies to confirm the molecular mechanism of the novel MET fusion in vitro or in vivo.
      Crizotinib has been recommended for treatment for MET exon 14 mutations or MET high-level amplification in advanced NSCLC. However, the therapeutic implications of MET fusions remain undetermined in NSCLC. In our study, the patient harboring PRKAR1A::MET fusion dramatically responded to the first-line monotherapy of crizotinib, and still achieved nearly complete response to second-line monotherapy of crizotinib after disease progress resulted from discontinued therapy. Previous case reports have documented MET fusions in patients with advanced NSCLC achieving a clinical benefit from crizotinib treatment.
      • Davies KD
      • Ng TL
      • Estrada-Bernal A
      • et al.
      Dramatic response to crizotinib in a patient with lung cancer positive for an HLA-DRB1-MET gene fusion.
      ,
      • Cho JH
      • Ku BM
      • Sun JM
      • et al.
      KIF5B-MET Gene rearrangement with robust antitumor activity in response to crizotinib in lung adenocarcinoma.
      ,
      • Plenker D
      • Bertrand M
      • de Langen AJ
      • et al.
      Structural alterations of MET trigger response to MET kinase inhibition in lung adenocarcinoma patients.
      ,
      • Kunte S
      • Stevenson J.
      A case of HLA-DRB1-MET rearranged lung adenocarcinoma with rapid response to crizotinib.
      Davies et al. reported a 74-year-old American female (non-smoker) with NSCLC with HLA-DRB1-MET gene fusion complete response (CR) to crizotinib.
      • Davies KD
      • Ng TL
      • Estrada-Bernal A
      • et al.
      Dramatic response to crizotinib in a patient with lung cancer positive for an HLA-DRB1-MET gene fusion.
      The second case of HLA-DRB1-MET gene fusion in NSCLC rapid response to crizotinib was described by Kunte and Stevenson.
      • Kunte S
      • Stevenson J.
      A case of HLA-DRB1-MET rearranged lung adenocarcinoma with rapid response to crizotinib.
      A 51-year-old Korean female (non-smoker) with NSCLC carrying KIF5B-MET gene fusion achieved a clinical benefit from crizotinib treatment during for ten months.
      • Cho JH
      • Ku BM
      • Sun JM
      • et al.
      KIF5B-MET Gene rearrangement with robust antitumor activity in response to crizotinib in lung adenocarcinoma.
      Plenker et al. indicated STARD3NL-MET gene fusions in a 62-year-old American female (non-smoker) with NSCLC partial response (PR) to crizotinib.
      • Plenker D
      • Bertrand M
      • de Langen AJ
      • et al.
      Structural alterations of MET trigger response to MET kinase inhibition in lung adenocarcinoma patients.
      These findings supported that crizotinib might be a promising drug for MET-translocated NSCLC.

      Conclusion

      In conclusion, we identified the first case of novel PRKAR1A::MET gene fusion in the patient with unresectable NSCLC who was negative for other known oncogenic drivers. The patient dramatically responded to the first-line monotherapy of crizotinib, and still achieved nearly complete response to second-line monotherapy of crizotinib after disease progress resulted from discontinued therapy. Therefore, this finding indicated that the novel PRKAR1A::MET fusion product might be an oncogenic driver in the patient's tumor and as novel targets for targeted therapies. The clinical trials are required to screen MET gene fusions via NGS-based large-panel test and/or NGS-based RNA fusion scan and confirm the efficacy of crizotinib treatment. Other MET inhibitors including cabozantinib, capmatinib, savolitinib, and tepotinib should be assessed in future clinical trials.

      Author Contributions

      Tonghui Ma and Xiaoli Li: Conception/design. Yang Yang and Xiaoli Li: Provision of study material or patients. Tonghui Ma, Yanxiang Zhang, Dandan Zhao: Collection and/or assembly of data. Yanxiang Zhang, Yang Yang: Data analysis and interpretation. Yanxiang Zhang: Manuscript writing. Tonghui Ma, Yanxiang Zhang, Xiaoli Li, Yang Yang, and Dandan Zhao: Final approval of manuscript.

      Acknowledgments

      We kindly thank to Jianhua Zhu and Dr. Baoming Wang (Genetron Health Co. Ltd.) providing professional bioinformatics analysis for this study.

      Disclosures

      YZ, TM, DZ were employed by Genetron Health (Beijing) Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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