|LETTER TO EDITOR
|Year : 2020 | Volume
| Issue : 2 | Page : 405-406
ALK inhibitors fuel ALK resistance mutation: Precision medicine takes on drug resistance
Gouri S Bhattacharyya1, Vivek Agarwala2, MV Chandrakanth2
1 Medical Oncology, Salt Lake City Medical Center, Kolkata, West Bengal, India
2 Department of Medical Oncology and Hemat-Oncology, Narayana Superspeciality Hospital and Cancer Institute, Kolkata, West Bengal, India
|Date of Submission||22-Mar-2020|
|Date of Acceptance||22-Mar-2020|
|Date of Web Publication||19-Jun-2020|
Gouri S Bhattacharyya
Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Bhattacharyya GS, Agarwala V, Chandrakanth M V. ALK inhibitors fuel ALK resistance mutation: Precision medicine takes on drug resistance. Cancer Res Stat Treat 2020;3:405-6
|How to cite this URL:|
Bhattacharyya GS, Agarwala V, Chandrakanth M V. ALK inhibitors fuel ALK resistance mutation: Precision medicine takes on drug resistance. Cancer Res Stat Treat [serial online] 2020 [cited 2021 Jan 27];3:405-6. Available from: https://www.crstonline.com/text.asp?2020/3/2/405/287279
Effective long-term treatment of ALK-rearranged lung cancers requires a mechanistic understanding of resistance to ALK-tyrosine kinase inhibitors (TKIs) so that rational therapies can be selected to combat resistance. The rapid pace of ALK-targeted drug development and the knowledge gained in parallel about resistance mechanisms illustrate the power of an iterative, systematic discovery process – at the bench and the bedside – to advance cancer research and transform patients' lives.
ALK-TKI resistance mechanisms are of two major classes: (i) ALK-dependent, “on-target” mechanisms including ALK secondary resistance mutations or amplification, where the tumor cell dependency on ALK signaling persists, and (ii) ALK-independent, “off-target” mechanisms including activation of bypass tracks and lineage changes, where the tumor cells effectively escape dependency on ALK. Unlike in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), where the T790M gatekeeper mutation is the predominant, clinically observed EGFR mutation causing resistance to first- and second-generation EGFR-TKIs, a much broader spectrum of on-target mutations has been identified in ALK-positive NSCLC treated with ALK-TKIs. This situation is reminiscent of the wide array of resistance mutations observed after treatment with the ABL inhibitor, imatinib in patients with chronic myelogenous leukemia. The difference in the spectrum of resistance mutations may be attributable to the genetic mechanisms of oncogene activation (i.e., gene rearrangements involving ALK or ABL, versus activating point mutations within the EGFR kinase domain) and/or the mode of TKI binding (i.e., to the inactive kinase conformation for imatinib and crizotinib, versus the active conformation for EGFR-TKIs, erlotinib, and gefitinib). Both these factors may influence the spectrum of drug-resistant mutations that arise in TKI-resistant patients.
In the setting of failure of a second-generation ALK-TKI, the development of a secondary ALK resistance mutation implies that ALK may still be functioning as an oncogenic driver. In patient-derived NSCLC cell lines with resistance to the second-generation ALK-TKIs, the third-generation ALK-TKI, lorlatinib, could inhibit the growth of cell lines harboring ALK resistance mutations but was inactive against those lines without ALK resistance mutations.
The article by Kapoor et al. brings out the ability of cancer to adapt to pharmacologic pressures and can be described in terms of tumor evolution, this stems from the intrinsic diversity, or heterogeneity of the the tumor and calls for the need of re-biopsy and next-generation sequencing in the longitudinal detection of tumor-specific mutations, to allow the definition of patterns of clonal evolution as a measurable characteristic of the cancer and to adapt the therapy to exploit and harness tumor evolution. More than 20 different ALK fusion partner genes have been reported.
The article, although a one-off case, does not discuss the use of liquid biopsy which may demonstrate more accumulation of ALK mutations during sequential treatment with next-generation ALK inhibitors, which promotes the formation of refractory compound mutations. The case study enhances our current understanding of the evolution of on-target resistance to ALK inhibitors and provides a blueprint for the rational design of the fourth-generation ALK inhibitors aimed at overcoming compound ALK mutations.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Lin JL, Riely GJ, Shaw AT. Targeting ALK: Precision medicine takes on drug resistance. Cancer Discov 2017;7:137-55.
Lin JJ, Shaw AT. Resisting resistance: Targeted therapies in lung cancer. Trends Cancer 2016;2:350-64.
Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, Pairish M, et al
. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem 2011;54:6342-63.
Kapoor A, Noronha V, Shetty O, Chougule A, Chandrani P, Patil VM, et al
. Molecular tumor board: Case 2– Evolution of resistance in anaplastic lymphoma kinase driven non-small-cell lung carcinoma. Cancer Res Stat Treat 2020;3:89-92.
Dagogo-Jack I, Rooney M, Lin JJ, Nagy RJ, Yeap BY, Hubbeling H, et al
. Treatment with next-generation ALK inhibitors fuels plasma ALK mutation diversity. Clin Cancer Res 2019;25:6662-70.
|This article has been cited by|
||Authorsę reply to Dubey et al. and Bhattacharyya et al.
| ||Akhil Kapoor,Vanita Noronha,Omshree Shetty,Anuradha Chougule,Pratik Chandrani,VijayM Patil,Amit Joshi,Nandini Menon,Rajiv Kumar,Mamta Gurav,Amit Kumar,Kumar Prabhash |
| ||Cancer Research, Statistics, and Treatment. 2020; 3(2): 406 |
|[Pubmed] | [DOI]|