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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 4  |  Page : 801-807

Resistance mechanisms to epidermal growth factor receptor inhibitors in non-small cell lung cancer

1 Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
2 Department of Molecular Pathology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
3 Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
4 Department of Radiodiagnosis, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India

Date of Submission24-Nov-2020
Date of Decision09-Dec-2020
Date of Acceptance10-Dec-2020
Date of Web Publication25-Dec-2020

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/crst.crst_357_20

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How to cite this article:
Bondili SK, Nandhana R, Noronha V, Joshi A, Patil V, Menon N, Chougule A, Shetty O, Kumar R, Chandrani P, Mahajan A, Chopade S, Prabhash K. Resistance mechanisms to epidermal growth factor receptor inhibitors in non-small cell lung cancer. Cancer Res Stat Treat 2020;3:801-7

How to cite this URL:
Bondili SK, Nandhana R, Noronha V, Joshi A, Patil V, Menon N, Chougule A, Shetty O, Kumar R, Chandrani P, Mahajan A, Chopade S, Prabhash K. Resistance mechanisms to epidermal growth factor receptor inhibitors in non-small cell lung cancer. Cancer Res Stat Treat [serial online] 2020 [cited 2022 May 25];3:801-7. Available from: https://www.crstonline.com/text.asp?2020/3/4/801/305016

  History Top

A 76-year-old woman with ischemic heart disease on dual antiplatelets and statins presented to us with 1-month history of cough and an episode of hemoptysis.

  Diagnosis Top

A contrast-enhanced computed tomography (CECT) scan showed a spiculated nodule in the right lower lobe of the lung [Figure 1]a. Whole-body positron-emission tomography CECT and magnetic resonance imaging did not reveal any evidence of distant metastasis. She underwent right lower lung lobectomy through video-assisted thoracoscopic surgery in January 2015. Postoperative histopathological examination revealed adenocarcinoma of the lung of size 2.2 cm × 2.5 cm × 2 cm, margins free of tumor; Stage IB (according to the American Joint Committee on Cancer (AJCC) staging system, 7th edition. She was kept under observation. She presented again in September 2017 with cough and breathlessness. A CECT scan revealed nodular right pleural thickening with multiple bilateral lung nodules and mild pericardial effusion [Figure 1]b. A CT-guided biopsy was done from the pleural nodule, and pathological and molecular analysis was performed. The histopathology revealed adenocarcinoma, which on immunohistochemistry (IHC) was positive for thyroid transcription factor-1 (TTF-1) and p53 and negative for WT-1, consistent with disease recurrence. While awaiting the results of the molecular testing, she was started on chemotherapy with one cycle of pemetrexed and carboplatin since she was bothered by the cough and breathlessness and her performance status was 2.
Figure 1: Contrast.enhanced computed tomography images showing (a) Right lower lobe mass at the time of diagnosis. (b) Right lower lobe mass with pleural effusion at the time of relapse. (c) Omental nodules at the time of progression on gefitinib. (d) Ascites and peritoneal disease at the time of progression on osimertinib

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  Molecular Testing Top

Real-time polymerase chain reaction

A TaqMan probe-based endpoint genotyping mutation analysis for the epidermal growth factor receptor (EGFR) by real-time polymerase chain reaction (RT-PCR) on the LC 480 II platform done on the pleural nodule biopsy sample at recurrence revealed an in-frame deletion in exon 19. She was started on tablet gefitinib 250 mg once daily in October 2017. Response evaluation CECT scans at three-monthly intervals showed a maintained partial response, with maximum toxicities of grade 2 skin rash and grade 1 paronychia. However, in January 2019, the disease progressed with a new onset of multiple pulmonary and omental nodules [Figure 1]c. Taqman-based RT-PCR on plasma cell-free DNA (cfDNA) was tested for the presence of the T790M mutation and was found to be negative. A repeat tissue biopsy from the omental nodule revealed adenocarcinoma; IHC showed strong and diffuse positivity for TTF-1; ALK-1 gene amplification was negative on using the Ventana D5F3 antibody clone. RT-PCR on the omental tissue biopsy was positive for the presence of the T790M mutation in the exon 20 of the EGFR gene. She received osimertinib 80 mg once daily from February 2019 with partial response clinically and radiologically (significant decrease in the pleural and parenchymal nodules as well as the omental nodules and mesenteric deposits) and no significant toxicity. She continued to do well on osimertinib until August 2020 when she developed abdominal distension and bloating sensation. CECT revealed stable pleural thickening and pleural effusion but a new onset of omental deposits, peritoneal nodularity, and gross ascites, which was suggestive of progressive disease [Figure 1]d. The ascitic fluid aspirate revealed adenocarcinoma [Figure 2]a and [Figure 2]b; an ascitic fluid cell block examination was sent for next-generation sequencing (NGS) analysis. While awaiting the results of the NGS, she was started on chemotherapy with pemetrexed and carboplatin, and response evaluation after four cycles of chemotherapy revealed stable disease.
Figure 2: Ascitic fluid cell block preparation at the time of progression on osimertinib showed metastatic adenocarcinoma (a; hematoxylin and eosin, ×20). Tumor cells were strongly and diffusely positive for TTF-1, confirming the pulmonary origin (b; 3,3'-diaminobenzidine [DAB], ×20). In addition, the tumor cells also expressed cytoplasmic and membranous staining (c; DAB, ×20) along with nuclear positivity for beta-catenin in few cells (d [arrowhead]; DAB, ×40)

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Next-generation sequencing

The SOPHiA solid-tumor solution molecular diagnostic assay was performed on the ascitic fluid cell block. This platform is used for the detection of DNA variants including single-nucleotide variants (SNVs) and indels in 42 genes, gene amplification events in 24 genes, and microsatellite instability (MSI) status of 6 unique loci. RNA alterations are identified using the Ampliseq for Illumina focus panel from 284 amplicons from 23 genes. Library preparation and paired-end sequencing by synthesis are performed using the Illumina MiSeq platform. The data are analyzed using the SOPHiA DDM and Illumina's Local Run Manager software. The NGS report is shown in [Table 1].
Table 1: Next-generation sequencing report of the patient after progression on osimertinib

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  Excerpts from the Discussion in the Molecular Tumor Board Top

The exon 19 deletion in the EGFR gene is a classical driver mutation in lung adenocarcinomas and confers sensitivity to the EGFR tyrosine kinase inhibitors (TKIs).[1] The EGFR exon 20 T790M mutation observed in our patient after treatment with gefitinib is an important and well-established mechanism of resistance to the first-generation TKIs.[2] In addition, an exon 20 C797S mutation was observed in this patient, which is the most common mechanism for development of resistance to third-generation TKIs like osimertinib.[3] It was further discussed to find out the type of C797S mutation (cis or trans) from the molecular laboratory. Moreover, the patient also harbored a mutation in the CTNNB1 gene that causes the activation of the wnt/beta-catenin signaling pathway and is a cause of acquired resistance to EGFR TKIs.[4] After discussion in the molecular tumor board, IHC for beta-catenin was done on the tissue biopsy, which showed nuclear positivity [Figure 2]c and [Figure 2]d. Nuclear staining for beta-catenin by IHC further validates the dysregulation of beta-catenin expression in this patient.[5] CTNNB1 mutations are seen in about 4%–5% of the patients with non-small cell lung cancer (NSCLC) and are associated with tumorigenesis and metastasis. Xenograft models have shown efficacy of niclosamide, an anti-parasitic drug, as an inhibitor of the beta-catenin pathway. Niclosamide is currently being tested in clinical trials for metastatic prostate and colon cancers.[6] Despite limited evidence, it was suggested in the molecular tumor board that niclosamide could be considered for this patient after she had exhausted the standard treatment options. The clinical course of the patient is summarized in [Table 2], with the details of molecular testing performed and the therapy administered.
Table 2: Timeline of tests and treatment for the patient

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  Mechanisms of Resistance to First-Generation Tyrosine Kinase Inhibitors Top

First- and second-generation TKIs yield durable responses in the majority of patients with lung cancer with sensitizing EGFR mutations.[7],[8] However, most patients eventually develop resistance to EGFR TKIs. Acquired resistance is defined as the systemic progression of disease while on continuous treatment with a TKI.[9] The mechanisms of resistance to EGFR TKIs can be grouped under two broad categories, as depicted in [Figure 3]. The most common mechanism of acquired resistance is the development of a secondary mutation in the EGFR gene, such as the T790M mutation in exon 20 (the gatekeeper mutation), which is seen in 50%–60% of the patients [Figure 4].[10] The T790M mutation (threonine to methionine substitution in the codon 790) occurs in the ATP-binding pocket of the tyrosine kinase receptor and increases the affinity of the protein for ATP, which eventually causes resistance to first- and second-generation TKIs.[2] Apart from T790M, few other mutations such as D761Y, L747S, T854A, and amplification of the EGFR gene can also lead to acquired resistance to TKIs [Table 3].
Figure 3: Resistance mechanism models to epidermal growth factor receptor tyrosine kinase inhibitors: secondary mutations in the epidermal growth factor receptor gene and oncogene switch (activation of the bypass signaling pathways) ACRONYMS: RTK-Receptor tyrosine kinase; EGFR-epidermal growth factor receptor; HER3-Human epidermal growth factor receptor 3; TKI-tyrsoine kinase inhibitor; STAT-signal transducer and activator of transcription proteins; ERK-extracellular-signal-regulated kinase

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Figure 4: Mechanisms of resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors

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Table 3: On-target resistance mechanisms to first/ second-generation epidermal growth factor receptor tyrosine kinase inhibitors

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Testing for T790M can be done by using liquid biopsy as well as tissue biopsy. Liquid biopsy for genotyping the cfDNA is less invasive, has a faster turnaround time, and is an acceptable alternative for tissue biopsy.[10] In a prospective study of 180 patients, Adrian et al. reported that digital droplet PCR-based testing of the cfDNA for T790M was associated with a sensitivity of 77.1%, specificity of 63.2%, and positive predictive value of 79%.[11] In view of low sensitivity, a negative liquid biopsy has to be confirmed with tissue biopsy.[12],[13] In a study by Chougule et al., the rate of detection of T790M was 81% in the bodily fluids versus 27% in the plasma. Hence, testing for T790M in the bodily fluids (cerebrospinal fluid, ascitic fluid, pleural fluid, etc.) is an alternative to a biopsy which has a higher sensitivity, probably because of higher concentration of malignant cell DNA in the bodily fluids than that in plasma.[14],[15]

  Non-Target-Mediated Resistance Top

Resistance to first- and second-generation TKIs can also arise as a result of alternative cellular pathways which activate the downstream signaling cascade and lead to tumor cell proliferation and survival. These pathways bypass the EGFR cellular pathways, thereby conferring resistance to TKIs. Some of the common bypass mechanisms include human epidermal growth factor receptor 2 (HER2) amplification; MET amplification; mutations in the BRAF, KRAS, and PIK3CA genes; and loss of PTEN [Table 5]. Small cell transformation and epithelial-to-mesenchymal transition are also well-established mechanisms, seen in about 10% and 1-2% of the patients, respectively, at the time of disease progression on TKIs [Figure 4].
Table 4: On-target resistance mechanisms to osimertinib and possible therapeutic options

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Table 5: Off-target resistance (bypass pathway) mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors

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Other mechanisms include HGF overexpression, FGF pathway alteration, loss of PTEN, mTOR mutation, and other EGFR alterations. In 10% of patients, no mechanism of resistance can be identified.

  Mechanisms of Resistance to Third-Generation Tyrosine Kinase Inhibitors Top

Third-generation TKIs include osimertinib and new molecules like rociletinib, olmutinib, nazartinib, lazertinib, avitinib, and CK-101. The superiority of osimertinib over chemotherapy in patients with T790M-positive lung cancer after failure of first generation TKIs was demonstrated in the AURA3 trial. In this phase III trial, the objective response rate was 71% and PFS was 10.1 months with osimertinib compared to an ORR of 31% and PFS of 4.4 months with chemotherapy.[16] The FLAURA trial established osimertinib as one of the standard first-line options in NSCLC with sensitizing EGFR mutation.[17] The ORR was 80% versus 76%, median PFS was 18.9 versus 10.2 months, and median overall survival was 38.6 versus 31.8 months for osimertinib versus first-generation TKI, respectively.[18]

Third-generation TKIs bind to the EGFR protein at the C797 residue, and a mutation of this residue confers resistance to TKI binding and is seen in up to 20% of the cases. This mutation causes steric hindrance which leads to the decreased binding affinity of all the third-generation TKIs (osimertinib, rociletinib, olmutinib, and nazartinib) with the tyrosine kinase domain and is the most common resistance mechanism in patients who progress on osimertinib.[19] When the C797S and T790M mutations occur on the same allele (cis conformation), they confer resistance to EGFR TKIs. However, when these mutations occur in different alleles (trans conformation), response to a combination of first- and third generation TKIs is reported.[20] A fourth-generation TKI, EA 1045 in combination with cetuximab, has shown promise in targeting T790M and C797S and is currently under evaluation in clinical trials.[21] Loss of T790M is another mechanism for resistance to osimertinib and is commonly seen in patients who progress early. Loss of T790M is usually associated with the activation of other bypass pathways like MET amplification and KRAS mutation.[22] Besides C797S, other point mutations in the EGFR gene such as G796, L792, L718, and G724 can also mediate resistance to osimertinib [Table 4].[19],[23]

EGFR-independent mechanisms of resistance include MET amplification (most common bypass pathway), HER2 amplification, RAS-MAPK pathway activation, PIK3CA mutation, and histological transformation [Figure 5][3] and possible therapeutic options are given in [Table 5].
Figure 5: Resistance mechanism to third-generation epidermal growth factor receptor tyrosine kinase inhibitors

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  CTNNB1 in Lung Cancer Top

The CTNNB1 gene encodes beta-catenin, a cytoplasmic protein which mediates cellular adhesion and is a component of the wnt/beta-catenin pathway which is involved in progenitor cell proliferation and survival. CTNNB1 mutations have been described in a variety of cancers including melanoma, colorectal cancer, mesothelioma, desmoid tumors, and others. In one study on 564 NSCLC patients with NSCLC, CTNNB1 mutations were seen in about 5.4% of patients with lung adenocarcinomas.[24] Females and nonsmoker patients were more likely to have this mutation which conferred a worse prognosis. Beta-catenin mutations are commonly detected by NGS. IHC may reveal loss of membrane staining of beta-catenin and abnormal nuclear staining.[5]

  Targeting Ctnnb1 Top

Studies have shown that beta-catenin is upregulated in EGFR-mutated NSCLC and leads to the constitutive activation of the wnt/beta-catenin pathway, thus contributing to tumorigenesis. Hence, beta-catenin mutations can confer resistance to EGFR TKIs by bypassing the inhibition of EGFR and activating the downstream signaling pathway.[25] In one study, inhibition of beta-catenin by XAV939 (a beta-catenin inhibitor) suppressed EGFR/T790M-mutated lung tumor. Thus, targeting the beta-catenin pathway may provide a novel strategy to prevent or overcome resistance to EGFR TKIs.[26]

Niclosamide, an antihelminthic drug, is an inhibitor of the wnt co-receptor LRP6 and has shown antiproliferative activity against several cancers such as prostate, colorectal, lung, and ovarian cancers by inhibiting multiple downstream pathways, namely wnt/beta-catenin, Notch, and nuclear factor kappa B pathways. Niclosamide is being evaluated in combination with enzalutamide in metastatic, castration-resistant prostate cancer (NCT02532114) and as a single agent in relapsed refractory metastatic colorectal cancer (NCT02519582). However, more studies are required to elucidate the role of niclosamide and to potentially improve the survival outcomes of patients.

  Conclusion Top

Mechanisms of resistance to EGFR TKIs are diverse. Re-biopsy and NGS of tumor tissue may help in identifying the resistance mechanism and thereby enable the selection of appropriate next-line therapy. This helps in expanding the arsenal of drugs available to target the tumor and improve the survival outcomes of patients.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.[49]

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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