Download PDF
CC BY 4.0 · Indian J Med Paediatr Oncol
DOI: 10.1055/s-0043-1776704
Case Report

Primary Resistance to ALK Inhibitors in a Patient with Nonsmall Cell Lung Cancer with ALK Rearrangement: A Case Report with Review of Literature

Suma Devaraj
1   Department of Medical Oncology, Institute of Medical Sciences and Sum Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, Odisha, India
,
Soumya Surath Panda 
1   Department of Medical Oncology, Institute of Medical Sciences and Sum Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, Odisha, India
,
Gourab Arun
1   Department of Medical Oncology, Institute of Medical Sciences and Sum Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, Odisha, India
,
Adya Kinkar Panda
2   Department of Radiology, Institute of Medical Sciences and Sum Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, Odisha, India
,
Debahuti Mohapatra
3   Department of Pathology, Institute of Medical Sciences and Sum Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, Odisha, India
,
Lalatendu Moharana
1   Department of Medical Oncology, Institute of Medical Sciences and Sum Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, Odisha, India
,
Spoorthy Kolluri
1   Department of Medical Oncology, Institute of Medical Sciences and Sum Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, Odisha, India
,
Sindhu Kilaru 
1   Department of Medical Oncology, Institute of Medical Sciences and Sum Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, Odisha, India
,
Swati Sucharita Mohanty 
1   Department of Medical Oncology, Institute of Medical Sciences and Sum Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, Odisha, India
,
Ghanashyam Biswas
1   Department of Medical Oncology, Institute of Medical Sciences and Sum Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, Odisha, India
› Author Affiliations Funding None.
› Further Information
Also available at
   Permissions and Reprints

Abstract

Anaplastic lymphoma kinase inhibitors (ALKi) are the standard of care for metastatic ALK-rearranged nonsmall cell lung cancer (NSCLC). Though most patients respond well to ALK, seldom there are instances where the disease progresses rapidly. Here, we present a case of a 41-years-old male diagnosed as NSCLC with ALK rearrangement. Despite being started on first- and second-generation ALK-targeted therapy, he had rapid disease progression ultimately succumbing to the disease within 3 months of diagnosis. We suspect that our patient has a variant of ALK, making him resistant to both first- and second-line targeted therapy. Subjecting such nonresponders to next-generation sequencing and identifying the variants might help to recognize a subset of patients among ALK+ NSCLC who will need intense monitoring and early institution of other therapies for a better outcome.

Keywords

EML4-ALK fusion protein - nonsmall cell lung cancer - resistance

Declaration of Patient Consent Form

Consent was obtained from the patient.


Ethics Approval

This study was approved by the institutional Ethics Committee, with Ref.no/DRI/IMS.SH/SOA/2021/097 dated 07.07.2021 (first approval) and Ref.no/IEC/IMS.SH/SOA/438 dated 13.10.2022 (approval renewal); and was conducted in accordance with the Declaration of Helsinki.


Declaration of Interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Authors' Contributions

All authors contributed equally to the writing, data, and figures of the final manuscript. The authors confirm that all authors have read and approved the manuscript.




Publication History

Article published online:
27 November 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

 

  • References

  • 1 Sung H, Ferlay J, Siegel RL. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71 (03) 209-249
    Google Scholar
  • 2 Soda M, Choi YL, Enomoto M. et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448 (7153) 561-566
    CrossrefPubMedGoogle Scholar
  • 3 Solomon BJ, Mok T, Kim DW. et al; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014; 371 (23) 2167-2177
    CrossrefPubMedGoogle Scholar
  • 4 Shaw AT, Bauer TM, de Marinis F. et al; CROWN Trial Investigators. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med 2020; 383 (21) 2018-2029
    CrossrefPubMedGoogle Scholar
  • 5 Camidge R, Kim HR, Ahn MJ. et al. Brigatinib vs crizotinib in patients with ALK inhibitor-naive advanced ALK+ NSCLC: updated results from the phase III ALTA-1L trial. Ann Oncol 2019; 30: ix195-ix196
    CrossrefGoogle Scholar
  • 6 Lin JJ, Zhu VW, Yoda S. et al. Impact of EML4-ALK variant on resistance mechanisms and clinical outcomes in ALK-positive lung cancer. J Clin Oncol 2018; 36 (12) 1199-1206
    CrossrefPubMedGoogle Scholar
  • 7 Choi YL, Takeuchi K, Soda M. et al. Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer Res 2008; 68 (13) 4971-4976
    CrossrefPubMedGoogle Scholar
  • 8 Takeuchi K, Choi YL, Soda M. et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res 2008; 14 (20) 6618-6624
    CrossrefPubMedGoogle Scholar
  • 9 Wong DW, Leung EL, So KK. et al; University of Hong Kong Lung Cancer Study Group. 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 (08) 1723-1733
    CrossrefPubMedGoogle Scholar
  • 10 Takeuchi K, Choi YL, Togashi Y. et al. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 2009; 15 (09) 3143-3149
    CrossrefPubMedGoogle Scholar
  • 11 Sanders HR, Li HR, Bruey JM. et al. Exon scanning by reverse transcriptase-polymerase chain reaction for detection of known and novel EML4-ALK fusion variants in non-small cell lung cancer. Cancer Genet 2011; 204 (01) 45-52
    CrossrefPubMedGoogle Scholar
  • 12 Wong DW, Leung EL, Wong SK. et al. A novel KIF5B-ALK variant in nonsmall cell lung cancer. Cancer 2011; 117 (12) 2709-2718
    CrossrefPubMedGoogle Scholar
  • 13 Takeuchi K, Soda M, Togashi Y. et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012; 18 (03) 378-381
    CrossrefPubMedGoogle Scholar
  • 14 Togashi Y, Soda M, Sakata S. et al. KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only. PLoS One 2012; 7 (02) e31323
    CrossrefPubMedGoogle Scholar
  • 15 Rikova K, Guo A, Zeng Q. et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007; 131 (06) 1190-1203
    CrossrefPubMedGoogle Scholar
  • 16 Jung Y, Kim P, Jung Y. et al. Discovery of ALK-PTPN3 gene fusion from human non-small cell lung carcinoma cell line using next generation RNA sequencing. Genes Chromosomes Cancer 2012; 51 (06) 590-597
    CrossrefPubMedGoogle Scholar
  • 17 Patel M, Malhotra J, Jabbour SK. Examining EML4-ALK variants in the clinical setting: the next frontier?. J Thorac Dis 2018; 10 (Suppl. 33) S4104-S4107
    CrossrefPubMedGoogle Scholar
  • 18 Gainor JF, Dardaei L, Yoda S. et al. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov 2016; 6 (10) 1118-1133
    CrossrefPubMedGoogle Scholar
  • 19 Lin JJ, Riely GJ, Shaw AT. Targeting ALK: precision medicine takes on drug resistance. Cancer Discov 2017; 7 (02) 137-155
    CrossrefPubMedGoogle Scholar
  • 20 Rihawi K, Alfieri R, Fiorentino M. et al. MYC amplification as a potential mechanism of primary resistance to crizotinib in ALK-rearranged non-small cell lung cancer: a brief report. Transl Oncol 2019; 12 (01) 116-121
    CrossrefPubMedGoogle Scholar
  • 21 Mengoli MC, Barbieri F, Bertolini F, Tiseo M, Rossi G. K-RAS mutations indicating primary resistance to crizotinib in ALK-rearranged adenocarcinomas of the lung: report of two cases and review of the literature. Lung Cancer 2016; 93: 55-58
    CrossrefPubMedGoogle Scholar
  • 22 Christopoulos P, Endris V, Bozorgmehr F. et al. EML4-ALK fusion variant V3 is a high-risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK+ non-small cell lung cancer. Int J Cancer 2018; 142 (12) 2589-2598
    CrossrefPubMedGoogle Scholar
  • 23 Noh KW, Lee MS, Lee SE. et al. Molecular breakdown: a comprehensive view of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer. J Pathol 2017; 243 (03) 307-319 DOI: 10.1002/PATH.4950.
    CrossrefPubMedGoogle Scholar
  • 24 Woo CG, Seo S, Kim SW. et al. Differential protein stability and clinical responses of EML4-ALK fusion variants to various ALK inhibitors in advanced ALK-rearranged non-small cell lung cancer. Ann Oncol 2017; 28 (04) 791-797
    CrossrefPubMedGoogle Scholar
  • 25 Li Y, Zhang T, Zhang J. et al. Response to crizotinib in advanced ALK-rearranged non-small cell lung cancers with different ALK-fusion variants. Lung Cancer 2018; 118: 128-133
    CrossrefPubMedGoogle Scholar