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Table of Contents
LETTER TO EDITOR
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 182-183

Path beyond tyrosine kinase inhibitors: Full of riddles and puzzles


Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India

Date of Submission28-Feb-2021
Date of Decision04-Mar-2021
Date of Acceptance04-Mar-2021
Date of Web Publication26-Mar-2021

Correspondence Address:
Ullas Batra
Department of medical oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_53_21

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How to cite this article:
Batra U, Nathany S. Path beyond tyrosine kinase inhibitors: Full of riddles and puzzles. Cancer Res Stat Treat 2021;4:182-3

How to cite this URL:
Batra U, Nathany S. Path beyond tyrosine kinase inhibitors: Full of riddles and puzzles. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Apr 23];4:182-3. Available from: https://www.crstonline.com/text.asp?2021/4/1/182/312113



We read with interest the article by Bondili et al. titled, “Resistance mechanisms to epidermal growth factor receptor inhibitors in non-small cell lung cancer.”[1] Following the results of the FLAURA trial,[2] with osimertinib being approved in the first line for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer, new challenges have emerged with respect to newer resistance mechanisms. The improved progression-free survival may be related to the improved penetration of the blood–brain barrier or suppression of the pretreatment EGFR T790M clones. However, the status of the pretreatment T790M mutation was not evaluated in patients enrolled in the FLAURA trial. The case discussed in Bondili et al.'s[1] article is interesting with respect to the disease course. However, whether pretreatment EGFR T790M clones were present cannot be ascertained as the patient underwent real-time polymerase chain reaction-based tissue genotyping, which usually has a 5% detection limit.[3]

In addition, reports from the literature suggest that T790M mutations can be detected using plasma cell-free DNA (cfDNA)-based genotyping at a median time of approximately 2 months before the actual progression as determined using the Response Evaluation Criteria in Solid Tumors.[4] Even though, in the case discussed by Bondili et al., T790M was not detected in the plasma cfDNA, other platforms with higher sensitivities could have detected it in the plasma, thus eliminating the need for a repeat omental biopsy. Post osimertinib resistance, the C797S mutation was detected along with an activating mutation in CTNNB1 gene, which is a part of the Wnt signaling pathway.[5] This was further confirmed by immunohistochemistry that revealed an abnormal nuclear localization of the beta catenin protein. However, whether C797S was in cis or trans with T790M has not been reported in this case. This information could have been easily obtained from the raw next-generation sequencing (NGS) data by evaluating the presence of these two mutations in the positive and negative strand reads using the Integrative Genomics Viewer (Broad Institute, USA) software. It has been described that patients harboring C797S in trans with T790M may benefit from combination therapy. Therefore, this information is crucial.

In addition, there is evidence in the literature that the CTNNB1-activating mutations co-exist with mutations in the TP53 and RB1 genes.[6] The NGS panel used in this case sequences 42 genes for the detection of DNA-based alterations. Therefore, it is important to note whether these genes were included in the panel. As transformation to small cell carcinoma may follow osimertinib therapy,[7] it is important to take into account the possible intratumor heterogeneity owing to which this transformation may have been missed. In this regard too, the presence/absence of TP53 or RB1 gene mutations is important, as they are commonly implicated in histological transformation to small cell carcinoma.

EGFR resistance mechanisms can be both primary and secondary, encompassing both EGFR-dependent and -independent mechanisms,[8],[9] which require a broader panel-based testing for detection, as seen here. The CTNNB1 activation would have otherwise been missed on sequential single-gene testing. Discussing the activation of the WNT signaling pathway as a resistance mechanism also necessitates the mention of the activation of YAP1,[5] which has been reported anecdotally post osimertinib therapy.

Finally, polymorphism in the B-cell lymphoma-2-like 11 (BCL2L 11) gene, a crucial mediator of apoptosis, which has been reported in 12% of the East Asians,[10] is important to detect. However, most of the times, it is not included in the NGS panels as it is a big deletion of ~2900 bp.[11] The use of BH3 mimetics to decrease this is being evaluated in preclinical studies.[12]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Bondili SK, Nandhana R, Noronha V, Joshi A, Patil V, Menon N, et al. Resistance mechanisms to epidermal growth factor receptor inhibitors in non-small cell lung cancer. Cancer Res Stat Treat 2020;3:801-7.  Back to cited text no. 1
  [Full text]  
2.
Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 2020;382:41-50.  Back to cited text no. 2
    
3.
Angulo B, Conde E, Suárez-Gauthier A, Plaza C, Martínez R, Redondo P, et al. A comparison of EGFR mutation testing methods in lung carcinoma: Direct sequencing, real-time PCR and immunohistochemistry. PLoS One 2012;7:e43842.  Back to cited text no. 3
    
4.
Zheng D, Ye X, Zhang MZ, Sun Y, Wang JY, Ni J, et al. Plasma EGFR T790M ctDNA status is associated with clinical outcome in advanced NSCLC patients with acquired EGFR-TKI resistance. Sci Rep 2016;6:20913.  Back to cited text no. 4
    
5.
Lee TF, Tseng YC, Nguyen PA, Li YC, Ho CC, Wu CW. Enhanced YAP expression leads to EGFR TKI resistance in lung adenocarcinomas. Sci Rep 2018;8:271.  Back to cited text no. 5
    
6.
Lazzari C, Gregorc V, Karachaliou N, Rosell R, Santarpia M. Mechanisms of resistance to osimertinib. J Thorac Dis 2020;12:2851-8.  Back to cited text no. 6
    
7.
Ma Q, Wang J, Ren Y, Meng F, Zeng L. Pathological mechanistic studies of osimertinib resistance in non-small-cell lung cancer cells using an integrative metabolomics-proteomics analysis. J Oncol 2020;2020:6249829.  Back to cited text no. 7
    
8.
Morgillo F, Della Corte CM, Fasano M, Ciardiello F. Mechanisms of resistance to EGFR-targeted drugs: Lung cancer. ESMO Open 2016;1:e000060.  Back to cited text no. 8
    
9.
Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Prabhash K. Epidermal growth factor receptor-mutated non-small-cell lung cancer: A primer on contemporary management. Cancer Res Stat Treat 2019;2:36-53.  Back to cited text no. 9
  [Full text]  
10.
Lin CH, Shen CY, Lee JH, Huang CS, Yang CH, Kuo WH, et al. High prevalence of the BIM deletion polymorphism in young female breast cancer in an East Asian Country. PLoS One 2015;10:e0124908.  Back to cited text no. 10
    
11.
Ma JY, Yan HJ, Gu W. Association between BIM deletion polymorphism and clinical outcome of EGFR-mutated NSCLC patient with EGFR-TKI therapy: A meta-analysis. J Cancer Res Ther 2015;11:397-402.  Back to cited text no. 11
    
12.
Cragg MS, Kuroda J, Puthalakath H, Huang DC, Strasser A. Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Med 2007;4:1681-89.  Back to cited text no. 12
    




 

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