Skip to main content
Top
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Case report

Activity of EGFR-tyrosine kinase and ALK inhibitors for EML4–ALK-rearranged non–small–cell lung cancer harbored coexisting EGFRmutation

Authors: Akihiko Miyanaga, Kumi Shimizu, Rintaro Noro, Masahiro Seike, Kazuhiro Kitamura, Seiji Kosaihira, Yuji Minegishi, Takehito Shukuya, Akinobu Yoshimura, Masashi Kawamoto, Shinichi Tsuchiya, Koichi Hagiwara, Manabu Soda, Kengo Takeuchi, Nobuyuki Yamamoto, Hiroyuki Mano, Yuichi Ishikawa, Akihiko Gemma

Published in: BMC Cancer | Issue 1/2013

Login to get access

Abstract

Background

The EML4–ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) fusion oncogene represents a novel molecular target in a small subset of non–small–cell lung cancers (NSCLCs). The EML4–ALK fusion gene occurs generally in NSCLC without mutations in epidermal growth factor receptor (EGFR) and KRAS.

Case presentation

We report that a case of EML4–ALK-positive NSCLC with EGFR mutation had a response of stable disease to both an EGFR tyrosine kinase inhibitor (EGFR-TKI) and ALK inhibitor.

Conclusions

We described the first clinical report of a patient with EML4–ALK-positive NSCLC with EGFR mutation that had a response of stable disease to both single-agent EGFR-TKI and ALK inhibitor. EML4–ALK translocation may be associated with resistance to EGFR-TKI, and EGFR signaling may contribute to resistance to ALK inhibitor in EML4–ALK-positive NSCLC.
Appendix
Available only for authorised users
Literature
1.
go back to reference Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007, 448 (7153): 561-566. 10.1038/nature05945.CrossRefPubMed Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007, 448 (7153): 561-566. 10.1038/nature05945.CrossRefPubMed
2.
go back to reference Takeuchi K, Choi YL, Soda M, Inamura K, Togashi Y, Hatano S, Enomoto M, Takada S, Yamashita Y, Satoh Y: Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Can Res. 2008, 14 (20): 6618-6624. 10.1158/1078-0432.CCR-08-1018.CrossRef Takeuchi K, Choi YL, Soda M, Inamura K, Togashi Y, Hatano S, Enomoto M, Takada S, Yamashita Y, Satoh Y: Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Can Res. 2008, 14 (20): 6618-6624. 10.1158/1078-0432.CCR-08-1018.CrossRef
3.
go back to reference Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes AJ, Choi HG, Kim J, Chiang D, Thomas R: EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Can Res. 2008, 14 (13): 4275-4283. 10.1158/1078-0432.CCR-08-0168.CrossRef Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes AJ, Choi HG, Kim J, Chiang D, Thomas R: EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Can Res. 2008, 14 (13): 4275-4283. 10.1158/1078-0432.CCR-08-0168.CrossRef
4.
go back to reference Mano H: Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer. Cancer Sci. 2008, 99 (12): 2349-2355. 10.1111/j.1349-7006.2008.00972.x.CrossRefPubMed Mano H: Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer. Cancer Sci. 2008, 99 (12): 2349-2355. 10.1111/j.1349-7006.2008.00972.x.CrossRefPubMed
5.
go back to reference Wong DW, Leung EL, So KK, Tam IY, Sihoe AD, Cheng LC, Ho KK, Au JS, Chung LP, Pik Wong M: The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 2009, 115 (8): 1723-1733. 10.1002/cncr.24181.CrossRefPubMed Wong DW, Leung EL, So KK, Tam IY, Sihoe AD, Cheng LC, Ho KK, Au JS, Chung LP, Pik Wong M: The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 2009, 115 (8): 1723-1733. 10.1002/cncr.24181.CrossRefPubMed
6.
go back to reference Perner S, Wagner PL, Demichelis F, Mehra R, Lafargue CJ, Moss BJ, Arbogast S, Soltermann A, Weder W, Giordano TJ: EML4-ALK fusion lung cancer: a rare acquired event. Neoplasia. 2008, 10 (3): 298-302.CrossRefPubMedPubMedCentral Perner S, Wagner PL, Demichelis F, Mehra R, Lafargue CJ, Moss BJ, Arbogast S, Soltermann A, Weder W, Giordano TJ: EML4-ALK fusion lung cancer: a rare acquired event. Neoplasia. 2008, 10 (3): 298-302.CrossRefPubMedPubMedCentral
7.
go back to reference Inamura K, Takeuchi K, Togashi Y, Nomura K, Ninomiya H, Okui M, Satoh Y, Okumura S, Nakagawa K, Soda M: EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol. 2008, 3 (1): 13-17. 10.1097/JTO.0b013e31815e8b60.CrossRefPubMed Inamura K, Takeuchi K, Togashi Y, Nomura K, Ninomiya H, Okui M, Satoh Y, Okumura S, Nakagawa K, Soda M: EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol. 2008, 3 (1): 13-17. 10.1097/JTO.0b013e31815e8b60.CrossRefPubMed
8.
go back to reference Shinmura K, Kageyama S, Tao H, Bunai T, Suzuki M, Kamo T, Takamochi K, Suzuki K, Tanahashi M, Niwa H: EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas. Lung Cancer. 2008, 61 (2): 163-169. 10.1016/j.lungcan.2007.12.013.CrossRefPubMed Shinmura K, Kageyama S, Tao H, Bunai T, Suzuki M, Kamo T, Takamochi K, Suzuki K, Tanahashi M, Niwa H: EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas. Lung Cancer. 2008, 61 (2): 163-169. 10.1016/j.lungcan.2007.12.013.CrossRefPubMed
9.
go back to reference Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Janne PA, Costa DB: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010, 363 (18): 1693-1703. 10.1056/NEJMoa1006448.CrossRefPubMedPubMedCentral Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Janne PA, Costa DB: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010, 363 (18): 1693-1703. 10.1056/NEJMoa1006448.CrossRefPubMedPubMedCentral
10.
go back to reference Nagai Y, Miyazawa H, Huqun , Tanaka T, Udagawa K, Kato M, Fukuyama S, Yokote A, Kobayashi K, Kanazawa M: Genetic heterogeneity of the epidermal growth factor receptor in non-small cell lung cancer cell lines revealed by a rapid and sensitive detection system, the peptide nucleic acid-locked nucleic acid PCR clamp. Cancer Res. 2005, 65 (16): 7276-7282. 10.1158/0008-5472.CAN-05-0331.CrossRefPubMed Nagai Y, Miyazawa H, Huqun , Tanaka T, Udagawa K, Kato M, Fukuyama S, Yokote A, Kobayashi K, Kanazawa M: Genetic heterogeneity of the epidermal growth factor receptor in non-small cell lung cancer cell lines revealed by a rapid and sensitive detection system, the peptide nucleic acid-locked nucleic acid PCR clamp. Cancer Res. 2005, 65 (16): 7276-7282. 10.1158/0008-5472.CAN-05-0331.CrossRefPubMed
11.
go back to reference Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010, 362 (25): 2380-2388. 10.1056/NEJMoa0909530.CrossRefPubMed Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010, 362 (25): 2380-2388. 10.1056/NEJMoa0909530.CrossRefPubMed
12.
go back to reference Popat S, Vieira de Araujo A, Min T, Swansbury J, Dainton M, Wotherspoon A, Lim E, Nicholson AG, O'Brien ME: Lung adenocarcinoma with concurrent exon 19 EGFR mutation and ALK rearrangement responding to erlotinib. J Thorac Oncol. 2011, 6 (11): 1962-1963. 10.1097/JTO.0b013e31822eec5e.CrossRefPubMed Popat S, Vieira de Araujo A, Min T, Swansbury J, Dainton M, Wotherspoon A, Lim E, Nicholson AG, O'Brien ME: Lung adenocarcinoma with concurrent exon 19 EGFR mutation and ALK rearrangement responding to erlotinib. J Thorac Oncol. 2011, 6 (11): 1962-1963. 10.1097/JTO.0b013e31822eec5e.CrossRefPubMed
13.
go back to reference Tiseo M, Gelsomino F, Boggiani D, Bortesi B, Bartolotti M, Bozzetti C, Sammarelli G, Thai E, Ardizzoni A: EGFR and EML4-ALK gene mutations in NSCLC: a case report of erlotinib-resistant patient with both concomitant mutations. Lung Cancer. 2011, 71 (2): 241-243. 10.1016/j.lungcan.2010.11.014.CrossRefPubMed Tiseo M, Gelsomino F, Boggiani D, Bortesi B, Bartolotti M, Bozzetti C, Sammarelli G, Thai E, Ardizzoni A: EGFR and EML4-ALK gene mutations in NSCLC: a case report of erlotinib-resistant patient with both concomitant mutations. Lung Cancer. 2011, 71 (2): 241-243. 10.1016/j.lungcan.2010.11.014.CrossRefPubMed
14.
go back to reference Sasaki T, Koivunen J, Ogino A, Yanagita M, Nikiforow S, Zheng W, Lathan C, Marcoux JP, Du J, Okuda K: A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res. 2011, 71 (18): 6051-6060. 10.1158/0008-5472.CAN-11-1340.CrossRefPubMedPubMedCentral Sasaki T, Koivunen J, Ogino A, Yanagita M, Nikiforow S, Zheng W, Lathan C, Marcoux JP, Du J, Okuda K: A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res. 2011, 71 (18): 6051-6060. 10.1158/0008-5472.CAN-11-1340.CrossRefPubMedPubMedCentral
15.
go back to reference Tanaka H, Hayashi A, Morimoto T, Taima K, Tanaka Y, Shimada M, Kurose A, Takanashi S, Okumura K: A case of lung adenocarcinoma harboring EGFR mutation and EML4-ALK fusion gene. BMC Cancer. 2012, 12 (1): 558-10.1186/1471-2407-12-558.CrossRefPubMedPubMedCentral Tanaka H, Hayashi A, Morimoto T, Taima K, Tanaka Y, Shimada M, Kurose A, Takanashi S, Okumura K: A case of lung adenocarcinoma harboring EGFR mutation and EML4-ALK fusion gene. BMC Cancer. 2012, 12 (1): 558-10.1186/1471-2407-12-558.CrossRefPubMedPubMedCentral
16.
go back to reference Kuo YW, Wu SG, Ho CC, Shih JY: Good response to gefitinib in lung adenocarcinoma harboring coexisting EML4-ALK fusion gene and EGFR mutation. J Thorac Oncol. 2010, 5 (12): 2039-2040. 10.1097/JTO.0b013e3181f43274.CrossRefPubMed Kuo YW, Wu SG, Ho CC, Shih JY: Good response to gefitinib in lung adenocarcinoma harboring coexisting EML4-ALK fusion gene and EGFR mutation. J Thorac Oncol. 2010, 5 (12): 2039-2040. 10.1097/JTO.0b013e3181f43274.CrossRefPubMed
17.
go back to reference Lee JK, Kim TM, Koh Y, Lee SH, Kim DW, Jeon YK, Chung DH, Yang SC, Kim YT, Kim YW: Differential sensitivities to tyrosine kinase inhibitors in NSCLC harboring EGFR mutation and ALK translocation. Lung Cancer. 2012, 77 (2): 460-463. 10.1016/j.lungcan.2012.04.012.CrossRefPubMed Lee JK, Kim TM, Koh Y, Lee SH, Kim DW, Jeon YK, Chung DH, Yang SC, Kim YT, Kim YW: Differential sensitivities to tyrosine kinase inhibitors in NSCLC harboring EGFR mutation and ALK translocation. Lung Cancer. 2012, 77 (2): 460-463. 10.1016/j.lungcan.2012.04.012.CrossRefPubMed
18.
go back to reference Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N: Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011, 29 (21): 2866-2874. 10.1200/JCO.2010.33.4235.CrossRefPubMed Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N: Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011, 29 (21): 2866-2874. 10.1200/JCO.2010.33.4235.CrossRefPubMed
19.
go back to reference Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T: Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010, 11 (2): 121-128. 10.1016/S1470-2045(09)70364-X.CrossRefPubMed Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T: Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010, 11 (2): 121-128. 10.1016/S1470-2045(09)70364-X.CrossRefPubMed
20.
go back to reference Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, Solomon B, Stubbs H, Admane S, McDermott U: Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009, 27 (26): 4247-4253. 10.1200/JCO.2009.22.6993.CrossRefPubMedPubMedCentral Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, Solomon B, Stubbs H, Admane S, McDermott U: Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009, 27 (26): 4247-4253. 10.1200/JCO.2009.22.6993.CrossRefPubMedPubMedCentral
Metadata
Title
Activity of EGFR-tyrosine kinase and ALK inhibitors for EML4–ALK-rearranged non–small–cell lung cancer harbored coexisting EGFRmutation
Authors
Akihiko Miyanaga
Kumi Shimizu
Rintaro Noro
Masahiro Seike
Kazuhiro Kitamura
Seiji Kosaihira
Yuji Minegishi
Takehito Shukuya
Akinobu Yoshimura
Masashi Kawamoto
Shinichi Tsuchiya
Koichi Hagiwara
Manabu Soda
Kengo Takeuchi
Nobuyuki Yamamoto
Hiroyuki Mano
Yuichi Ishikawa
Akihiko Gemma
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-262

Other articles of this Issue 1/2013

BMC Cancer 1/2013 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine