ceritinib and Adenocarcinoma-of-Lung

Lung cancer is the most common in incidence and mortality worldwide. With the development of next generation sequencing (NGS) detection technology, more and more patients with rare anaplastic lymphoma kinase (ALK) fusion mutations were detected. A case of advanced lung adenocarcinoma with rare COX7A2L-ALK (C2:A20) fusion detected by NGS was reported in Peking Union Medical College Hospital, and all cases with rare ALK fusion mutations were searched from medical datebase from January 1, 2014 to March 31, 2021, to investigate the treatment of rare ALK fusion mutations with ALK inhibitors. The best response of the patient was assessed as partial response (PR) with Ceritinib treatment. By literature review, 22 cases of rare ALK fusion were reported in 19 articles. Combined with this case, 23 cases were analyzed. The objective response rate (ORR) was 82.6% (19/23) and disease control rate (DCR) was 95.7% (22/23) for rare ALK fusions patients treated with ALK inhibitors. Lung adenocarcinoma patients with rare ALK fusion could benefit from ALK inhibitors.
.. 【中文题目：罕见COX7A2L-ALK融合突变
晚期肺腺癌1例病例报告并文献复习】 【中文摘要：肺癌是全世界发病率和死亡率最高的肿瘤，随着下一代测序（next generation sequencing, NGS）检测技术的发展，越来越多的罕见间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）融合突变患者被检测出来。本文报道了北京协和医院收治的1例罕见COX7A2L-ALK（C2:A20）融合突变的肺腺癌晚期患者，同时检索2014年1月1日-2021年3月31日发表的罕见ALK融合突变的病例报道，探讨ALK抑制剂对罕见ALK融合突变患者的疗效。本例患者一线给予口服塞瑞替尼后病情好转，疗效评价为部分缓解（partial response, PR）。通过上述检索方法检索出符合文献19篇，共报道22例罕见ALK融合突变，结合本例，对23例进行汇总分析。分析结果显示，ALK抑制剂对罕见ALK融合突变的客观有效率为82.6%（19/23），疾病控制率为95.7%（22/23）。罕见ALK融合突变晚期肺腺癌患者可以从ALK抑制剂治疗中受益。
】 【中文关键词：罕见ALK融合突变；ALK抑制剂；肺肿瘤；COX7A2L-ALK融合突变】.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Crizotinib; Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Protein Kinase Inhibitors

ALK translocation is the 3rd most frequent genetic aberration in lung adenocarcinoma, and several inhibitors are now clinically available in first and second line settings. Accordingly, molecular diagnostics of ALK-positive lung cancer is very important and can be done with the rational combination of several methods. All international recommendations suggest that, except for cytological samples, screening technology for ALK-positive tumors is immunohistochemistry using a validated test. It is highly recommended that in case of ALK protein positive samples gene translocation must be confirmed by fluorescent in situ hybridization (FISH). In case of cytological samples FISH technique must be used as ALK diagnostics. In equivocal cases the genetic alteration of ALK can be confirmed by alternative molecular techniques such as next generation sequencing or RNAbased PCR methods. Upon administration of ALK inhibitors, acquired resistance is frequent which is mostly due to ALK amplification and/or mutation. It is evident that the diagnostics of these secondary ALK gene alterations must be done from recurrent tumors or circulating nucleic acids.. Az ALK gén transzlokációja a harmadik leggyakoribb, terápiás szempontból hasznosítható genetikai eltérés a tüdõ adenokarcinómáiban, és manapság már elsõ- és másodvonalú terápiákban több inhibitor áll rendelkezésre. Ezen okoknál fogva nagy jelentõsége van az ALK-pozitív tüdõrák molekuláris diagnosztikájának, amit több módszer racionális kombinációjával lehet végezni. A nemzetközi ajánlások megegyeznek abban, hogy a citológiai minták kivételével más típusú formalinfixált, paraffinos anyagok esetében az ALK-pozitív esetek szûrése a protein kimutatásának validált immunhisztokémiai módszerével történik. Az ALK proteinre pozitív esetekben a géntranszlokáció jelenlétét fluoreszcens in situ hibridizációval (FISH) célszerû megerõsíteni. Citológiai minták esetében az ALK gén transzlokációját elsõdlegesen FISH-módszerrel kell végezni. A kérdéses eredményû esetekben a genetikai eltérés tisztázására újgenerációs szekvenálást vagy RNS-alapú PCR-technikákat lehet alkalmazni. Az ALK-inhibitorok klinikai alkalmazása során gyakran alakul ki rezisztencia, aminek leggyakoribb oka az ALK gén amplifikációja és/vagy mutációi. Ezek molekuláris diagnosztikájának alapja a recidív daganatszövet vagy a vérben keringõ nukleinsav kell, hogy legyen.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Biopsy, Needle; Carbazoles; Crizotinib; Early Detection of Cancer; Gene Expression Regulation, Neoplastic; Humans; Hungary; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung Neoplasms; Molecular Targeted Therapy; Piperidines; Polymerase Chain Reaction; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Risk Assessment; Sulfones; Survival Analysis; Translocation, Genetic; Treatment Outcome

If anaplastic lymphoma kinase (ALK) gene rearrangement in lung cancer is identified, ALK-tyrosine kinase inhibitors (ALK-TKIs) can be an effective treatment. However, the details of drug-induced lung injury (DILI) caused by ALK-TKI, which can be a serious side effect of ALK-TKIs, remains unclear. This study aimed to investigate the clinical features and the onset risk factors of DILI by ALK-TKIs in clinical practice.. The clinical features of 56 consecutive patients who received crizotinib, alectinib, and/or ceritinib at our hospital from 2012 to 2018 were retrospectively examined. Among these, patients diagnosed with DILI due to ALK-TKIs were evaluated in terms of clinical features and parameters. Each clinical parameter before the administration of ALK-TKIs was compared between the DILI onset group and the non-onset group.. A total of seven cases were diagnosed with DILI due to ALK-TKIs; no DILI-related deaths were observed. Chest computed tomography (CT) scan findings identified six patients with the organizing pneumonia (OP) pattern and one with the hypersensitivity pneumonia pattern. The onset of DILI was significantly different in patients age ≥ 64 years and with a creatinine clearance <80 mL/minute.. Extra caution for DILI due to ALK-TKIs may be needed when recommending ALK-TKIs for patients over 64 years of age, or with decreased renal function. CT images of the majority of patients with DILI by ALK-TKIs show an OP pattern.. Significant findings of the study: Extra caution is needed when recommending ALK-TKIs for patients over 64 years of age or those with decreased renal function. Computed tomography images of the majority of patients with DILI by ALK-TKIs show an OP pattern.. The same or a different ALK-TKI may be considered as a treatment option after the onset of DILI, based on careful judgment.

Topics: Adenocarcinoma of Lung; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Squamous Cell; Crizotinib; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Lung Injury; Lung Neoplasms; Male; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Risk Factors; Sulfones; Survival Rate

Anaplastic lymphoma kinase (ALK) inhibitors have significant efficacies in ALK-rearranged non-small cell lung cancers (NSCLC). In regard to pediatric NSCLC patients, however, there is a paradox in that on the one hand, they may have a higher probability of ALK-rearrangement positive, but on the other hand, there is no sufficient data for efficacies of ALK inhibitors in pediatric NSCLC patients. Here, we present an 11-year-old boy diagnosed with metastatic ALK-rearranged lung adenocarcinoma. He was treated with ceritinib 450 mg with food once daily and has obtained near complete response in 18th month, with a largely regressed intrathoracic lesion and only localized residual distant metastatic disease. Meanwhile, he showed continued good tolerance after a short period of side effects at the beginning of the dose. This is the first report of the use of ceritinib in pediatric patient with NSCLC.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Child; Humans; Lung Neoplasms; Male; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Ceritinib is a new anaplastic lymphoma kinase (ALK) inhibitor that has shown greater potency in patients with advanced ALK-rearranged non-small cell lung cancer, including those who had disease progression in crizotinib treatment. Here we reported, after several months of ceritinib treatment, two patients with advanced ALK-rearranged pulmonary adenocarcinoma exhibited a spectrum of respiratory symptoms like cough and dyspnea, with significantly higher inflammatory indicators. Chest computed tomography (CT) showed multiple bilateral and peripheral lesions in lungs. The prior considerations taken into account were disease progression or infection. However, biopsies of the pulmonary nodules revealed features of granulomatous inflammation without definite cancer cells. We documented for the first time that ceritinib might be associated with pulmonary granulomatous inflammation, and clinicians should be alert to the possibility that the rare adverse event emerged during ceritinib treatment.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Disease Progression; Humans; Inflammation; Lung; Lung Neoplasms; Pneumonia; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Anaplastic lymphoma kinase (ALK) gene fusion, an important driver gene alteration leading to the development of lung cancer, occurs in 5% of nonsmall cell lung cancer (NSCLC) cases in China. In addition to echinoderm microtubule-associated protein-like 4 (EML4)-ALK, which is the most common type of ALK fusion, various fusion partner genes have been identified in recent years. However, ALK intergenic breakpoint fusions confound fusion detection and targeted treatment.. A 40-year-old woman presented to our hospital with a 2-month history of a cough.. Based on the right hilar lymph node biopsy and positron emission tomography computed tomography (PET-CT) examination, the patient was diagnosed with "stage IV lung adenocarcinoma" showing metastases in the mediastina, right hilar lymph nodes, and C7 vertebral body. A rare solute carrier family 8 member A1 (SLC8A1) downstream intergenic region ALK fusion was identified in biopsy specimens using next-generation sequencing (NGS).. The patient received first-line molecular-targeted therapy (ceritinib).. After nearly 9 months, the best evaluation of partial remission (PR) was obtained.. This is the first clinical evidence of advanced NSCLC due to a rare SLC8A1 downstream intergenic region ALK fusion that has been effectively treated with ceritinib. Whether this finding represents an inherent property of this fusion protein or its unique clinicopathological characteristics in patients carrying this fusion protein remains to be investigated. Moreover, the patient's durable response to ceritinib and future resistance mechanisms require further follow-up.

Topics: Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; DNA, Intergenic; Female; Gene Fusion; Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Patients with

Topics: Adenocarcinoma of Lung; Adult; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Immune Checkpoint Inhibitors; Lactams; Lung Neoplasms; Male; Mutation; Neoplasm Staging; Nivolumab; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyrimidines; Sulfones; Time Factors; Treatment Outcome; Tumor Microenvironment

The treatment of stage IIIB non-small cell lung cancer (NSCLC) is complicated, the best strategy is chosen individually and surgery is usually not recommended. A 50-year-old female was diagnosed with locally advanced lung adenocarcinoma (stage IIIB, T2bN3M0). Fluorescence in situ hybridization (FISH) analysis revealed an ALK rearrangement. Crizotinib was administered and progression was seen after five months. The patient then received ceritinib with a palliative intent, which led to downstaging (IIIA[N2]) with a radiological and metabolic response. Right lower lobe lobectomy was performed at 12 months post-surgery, and the patient is still disease-free according to the last computed tomography (CT) scan. The unintended downstaging from ceritinib provided a chance for resection in our patient who had ALK-positive stage IIIB NSCLC after the failure of first-line crizotinib, indicating potential usage of ceritinib in the neoadjuvant setting. Future perspective trials are warranted to investigate the role of ceritinib in earlier stages as a primary drug.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Middle Aged; Neoadjuvant Therapy; Pneumonectomy; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangements are found in ~ 5% of patients with non-small cell lung cancer (NSCLC). Several tyrosine kinase inhibitors (TKIs) have been developed for treatment of so-called ALK-positive NSCLC. In cases of tumor progression during treatment with second-generation ALK-TKIs, such as alectinib, brigatinib, or ceritinib, National Comprehensive Cancer Network guidelines propose a switch to lorlatinib, a third-generation ALK-TKI, or to cytotoxic chemotherapy. However, they do not mention switching to other second-generation ALK-TKIs. Here, we present a rare case of a 53-year-old Japanese woman, who had never smoked, with ALK-positive lung adenocarcinoma who survived alectinib-resistant postoperative recurrence for 4 years by switching to ceritinib. She underwent curative resection for lung adenocarcinoma, but the cancer recurred at the bronchial stump and mediastinal lymph nodes. After platinum-doublet chemotherapy, the patient still had a single growing liver metastasis, but the tumor was found to harbor EML4-ALK rearrangement. Therefore, the patient started to take ALK-TKIs. Alectinib was the second ALK-TKI used to treat this patient. Alectinib shrank the liver metastasis, which was surgically resected. The tumor relapsed again during continued treatment with alectinib, which was switched to ceritinib. Ceritinib was effective for the relapsed tumor and treatment continued well for 4 years. This case report suggests that, in case of tumor progression during treatment with a second-generation ALK-TKI, switching to another second-generation ALK-TKI may be one of the treatment options. Further analyses are warranted to find robust markers to determine which ALK-TKI is best for each patient.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Pneumonectomy; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Anaplastic lymphoma kinase (ALK) inhibitors have been approved for patients with ALK-rearrangement lung cancer. The effect is superior to the standard first-line therapy of pemetrexed plus platinum-based chemotherapy. However, ALK inhibitors are associated with rare and sometimes fatal adverse events. Organizing pneumonitis (OP) is a rare and serious adverse event usually caused by ceritinib, and it is easily misdiagnosed as infectious pneumonia, metastasis, or cancer progression.. A 56-year-old female presented with chest tightness and dyspnea for more than 10 days. She was previously healthy with no significant medical history. Workup including chest computed tomography (CT), pathological examination of a biopsy specimen, and next-generation sequencing was consistent with a diagnosis of IVA ALK-rearrangement lung adenocarcinoma. She was treated with pemetrexed plus platinum-based chemotherapy and crizotinib concurrently, followed by maintenance therapy with crizotinib alone and she had an almost complete response. However, about 26 months after beginning treatment she developed multiple brain metastases. Crizotinib was discontinued and she was begun on ceritinib. After about 3 months the brain metastases had almost complete response. After 5 months of ceritinib, however, multiple patchy lesions appeared in the bilateral upper lungs.. Treatment with antibiotics had no effect and blood and sputum cultures are negative. A CT-guided biopsy of the upper lung was performed, and pathological hematoxylin-eosin staining and immunohistochemical studies were consistent with OP.. Ceritinib was discontinued, she was begun on prednisone 0.5 mg/kg orally every day, and regular follow-up is necessary.. CT of the chest 2 and 4 weeks after beginning prednisone showed the lung lesions to be gradually resolving, and she was continued on prednisone for 2 months and gradually reduced the dose of prednisone every 2 weeks. No related adverse events were occurred in patient.. OP must be differentiated from infectious pneumonia, metastasis, or cancer progression. The mechanism of OP is still unknown and needs further research. Biopsy plays a role in making a diagnosis of OP. In our patient, discontinuing ceritinib and treating her with prednisone resulted in a good outcome.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biopsy; Brain Neoplasms; Crizotinib; Cryptogenic Organizing Pneumonia; Drug Substitution; Enzyme Inhibitors; Female; High-Throughput Nucleotide Sequencing; Humans; Lung; Lung Neoplasms; Middle Aged; Pemetrexed; Prednisone; Pyrimidines; Sulfones; Tomography, X-Ray Computed; Treatment Outcome

A 40-year-old Japanese man with advanced pulmonary adenocarcinoma harboring anaplastic lymphoma kinase (ALK)-rearranged was administered the selective ALK inhibitor ceritinib as a third-line treatment and continued treatment for nine months. After fourth-line treatment, we performed rechallenge with ceritinib as a fifth-line treatment. On day 54 after rechallenge, the patient developed acutely deteriorating dyspnea. Chest computed tomography showed extensive ground-glass opacities. We diagnosed him with ceritinib-induced interstitial lung disease (ILD) and initiated methylprednisolone pulse therapy. To our knowledge, this is the first report of ceritinib-induced ILD in a Japanese patient. Since it may newly emerge with rechallenge therapy, close attention is necessary.

Topics: Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Tomography, X-Ray Computed

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for development of various tumor types. In this study, we synthesized a series of novel 2,4-diarylaminopyrimidine derivatives possessing a unique N-(3-pyridinylmethyl)urea moiety as ALK inhibitors. The most promising analog 5m bearing a 3-methoxy-4-morpholinophenyl substituent significantly inhibited proliferation of ALK positive H3122 and Karpas-299 cells with IC

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Proliferation; Drug Stability; Female; Fibroblasts; Humans; Lung Neoplasms; Mice, Inbred BALB C; Microsomes, Liver; Molecular Docking Simulation; Molecular Structure; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Structure-Activity Relationship; Xenograft Model Antitumor Assays

Pancreatic metastasis from non-small cell lung cancer (NSCLC) is usually asymptomatic or presents with abdominal pain, acute pancreatitis, or jaundice. A lung primary is associated with worse survival compared to pancreatic metastases from other organs. Surgical treatment of solitary metastasis to the pancreas from NSCLC has been reviewed in several studies, one of which had a notable disease-free interval. To our knowledge, there are no prior reports of targeted therapy of pancreatic metastasis of NSCLC followed by a significant response. Herein we report the case of a 31-year-old female with a solitary pancreatic metastasis from ALK-rearranged lung adenocarcinoma despite treatment with chemotherapy and crizotinib; she presented with symptoms of hyperglycemia. Targeted therapy with ceritinib (LDK378) led to symptomatic improvement and a significant radiologic response in the lung and pancreas, but not in the brain.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Humans; Hyperglycemia; Lung Neoplasms; Magnetic Resonance Imaging; Molecular Targeted Therapy; Mutation; Neoplasm Metastasis; Neoplasm Staging; Protein Kinase Inhibitors; Pyrimidines; Radiotherapy, Adjuvant; Receptor Protein-Tyrosine Kinases; Sulfones; Tomography, X-Ray Computed; Translocation, Genetic; Treatment Outcome

We report an ALK-rearranged adenocarcinoma of the lung presenting as a pituitary metastasis, clinically simulating a pituitary adenoma. The patient, a 50 year-old, former-smoking woman was admitted with a Parinaud's syndrome characterized by progressive oculomotor impairment of visual verticality, bitemporal hemianopsia and nystagmus. Imaging studies showed a sellar tumor and the biopsy revealed a TTF-1 and napsin positive lung adenocarcinoma strongly expressing synaptophysin and CD56, also harboring ALK rearrangement. A subsequent CT scan disclosed the primary lung mass of the left upper lobe. The patient progressed after 4 cycles of cisplatin/pemetrexed as first line treatment, but showed a partial response and a significant clinical benefit from the combination of ceritinib and nivolumab in a phase Ib trial. Despite its central nervous system tropism, ALK-rearranged adenocarcinoma manifesting with pituitary gland involvement was never reported. Second generation ALK inhibitors seem the best therapeutic strategy.

Topics: Adenocarcinoma of Lung; Adenoma; Anaplastic Lymphoma Kinase; Biomarkers, Tumor; Female; Gene Rearrangement; Humans; Immunohistochemistry; Lung Neoplasms; Middle Aged; Neoplasm Metastasis; Pituitary Gland; Pituitary Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Clinical outcomes of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer according to ALK fusion variants are not clear. We aimed to investigate the prevalence of ALK fusion variants and to compare clinical outcomes according to ALK fusion variants.. A retrospective analysis was conducted on patients with advanced ALK-rearranged adenocarcinoma treated with chemotherapy and ALK inhibitors. ALK rearrangement was identified by fluorescence in situ hybridization and confirmed by immunohistochemistry. Peptide nucleic acid-mediated quantitative polymerase chain reaction assays, designed to detect 28 types of echinoderm microtubule-associated protein-like 4 (EML)-ALK rearrangements, were performed. Clinicopathological analysis and treatment outcomes with platinum-based chemotherapy, pemetrexed therapy, and ALK inhibitors-including crizotinib and ceritinib-were evaluated.. A total of 52 patients with ALK-rearranged lung adenocarcinoma were enrolled. EML4-ALK variant 1 (v1) was the most common variant (38.5 %) followed by the non-EML4 variant (36.5 %), EML4-ALK variant 3a/b (19.2 %), and EML4-ALK variant 2 (5.8 %). No clinicopathological distinction was found between the different ALK fusion variants. Treatment response rates for each therapeutic agent did not differ according to ALK fusion variant. However, EML4 variants, especially v1, showed significantly longer progression-free survival (PFS) on pemetrexed treatment than did non-EML4 variants (median 31.1 months versus 5.7 months, P = 0.003). PFS with platinum-based chemotherapy and ALK inhibitors did not differ according to ALK fusion variant. Multivariate survival analysis using Cox's regression model revealed v1 as the only predictive factor for prolonged PFS on pemetrexed.. Among ALK fusion variants, v1 is the most common subtype. It showed superior progression-free survival on pemetrexed than did non-EML4 variants. No survival difference was demonstrated between variants treated with crizotinib or ceritinib.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Aged; Anaplastic Lymphoma Kinase; Crizotinib; Disease-Free Survival; Female; Gene Rearrangement; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Mutation; Oncogene Proteins, Fusion; Pemetrexed; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Treatment Outcome

The echinoderm microtubule associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was identified in patients with non-small cell lung cancer. To the best of our knowledge, there are only three cell lines harboring the EML4-ALK fusion gene, which have contributed to the development of therapeutic strategies. Therefore, we tried to establish a new lung cancer cell line harboring EML4-ALK.. A 61-year-old Japanese female presented with chest discomfort. She was diagnosed with left lung adenocarcinoma with T4N3M1 Stage IV. Although she was treated with chemotherapy, her disease progressed with massive pleural effusion. Because the EML4-ALK rearrangement was found in a biopsied specimen using fluorescence in situ hybridization, she was treated with crizotinib. She did well for 3 months.. Tumor cells were obtained from the malignant pleural effusion before treatment with crizotinib. Cells continued to proliferate substantially for several weeks. The cell line was designated ABC-11. The EML4-ALK fusion protein and genes were identified in ABC-11 cells using fluorescence in situ hybridization and immunohistochemistry, respectively. ABC-11 cells were sensitive to crizotinib and next-generation ALK inhibitors (ceritinib and AP26113), as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Phosphorylated ALK protein and its downstream signaling were suppressed by treatment with crizotinib in western blotting. Furthermore, we could transplant ABC-11 cells subcutaneously into BALB/c nu/nu mice.. We successfully established a new lung adenocarcinoma cell line harboring the EML4-ALK fusion gene. This cell line could contribute to future research of EML4-ALK-positive lung cancer both in vivo and in vitro.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Cell Cycle Proteins; Cell Line, Tumor; Crizotinib; Female; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Microtubule-Associated Proteins; Middle Aged; Oncogene Proteins, Fusion; Pleural Effusion, Malignant; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Serine Endopeptidases; Signal Transduction; Sulfones