|Year : 2016 | Volume
| Issue : 7 | Page : 131-137
Current mechanism of acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors and updated therapy strategies in human nonsmall cell lung cancer
Kaixian Zhang, Qianqian Yuan
Department of Oncology, Tengzhou Central People's Hospital, Tengzhou, Shangdong, P.R. China
|Date of Web Publication||21-Feb-2017|
Department of Oncology, Tengzhou Central People's Hospital, Xingtan Road No. 181, Tengzhou 277599, Shangdong
Source of Support: None, Conflict of Interest: None
Lung cancer continues to be a major health problem and the most common cancer-related mortality worldwide with about 80%–85% patients suffering from nonsmall cell lung cancer (NSCLC). More than 80% of NSCLC cases are often diagnosed as advanced stage and harbor epidermal growth factor receptor (EGFR) activating mutation. Although great success in initial response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are found in EGFR-mutant NSCLC patients, acquired resistance usually occurs on the continuous treatment. Here, we provide an overview on the mechanism of acquired resistance to EGFR-TKIs in NSCLC therapy as well as current preclinical and clinical evidence of new therapy strategies and inhibitors in the treatment of NSCLC. Many studies have shown that original or induced T790M mutation, human EGFR 2 amplification, and activated secondary signaling such as MET amplification or phosphatidylinositol 3-kinase mutation can lead to acquired resistance to EGFR-TKIs. In addition, transformation from NSCLC to SCLC or conferred epithelial to mesenchymal transition has also been identified as mechanisms of acquired resistance to EGFR-TKIs. Increasing evidence has proven that non-coding RNA including long noncoding RNAs and microRNAs or new EGFR mutation is involved in acquired resistance. Preclinical and clinical Phase 1–3 evidence on combination drug therapy or new generation inhibitors with different tumor-targeting approaches have made those strategies the promising options for EGFR-TKI-resistant NSCLC therapy. This review aims to get deep insight into providing a state-of-the-art overview of the recent advances in the mechanisms of acquired resistance and new strategies for targeted cancer therapy in EGFR-TKI-resistant NSCLC.
Keywords: Acquired resistance, epidermal growth factor receptor-tyrosine kinase inhibitors, mechanisms, new strategy, nonsmall cell lung cancer
|How to cite this article:|
Zhang K, Yuan Q. Current mechanism of acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors and updated therapy strategies in human nonsmall cell lung cancer. J Can Res Ther 2016;12, Suppl S3:131-7
|How to cite this URL:|
Zhang K, Yuan Q. Current mechanism of acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors and updated therapy strategies in human nonsmall cell lung cancer. J Can Res Ther [serial online] 2016 [cited 2021 Mar 6];12:131-7. Available from: https://www.cancerjournal.net/text.asp?2016/12/7/131/200613
| > Introduction|| |
Lung cancer ranked the first in males and top five in females of newly diagnosed cancer cases and the cancer-related deaths worldwide with a generally grim prognosis, with over 80% of the patients falling into the category of nonsmall cell lung cancer (NSCLC). NSCLC is often diagnosed as advanced stage, and the opportunity for surgical resection is lost. Chemotherapies with either mono application or combo-administration of platinum-based or other cytotoxic chemicals are usually traditional strategies for NSCLC treatment. However, the objective efficacy of these strategies was often unsatisfactory, with median overall survival usually <1 year.
In approximately 30% of the NSCLC patients whose tumors harbor epidermal growth factor receptor (EGFR) activating mutation, EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib show tremendous success in the past decades., However, despite an initial dramatic response to EGFR-TKIs, acquired resistance usually occurred when patients were treated with EGFR inhibitors for 10–14 months. Multiple mechanisms of acquired resistance to EGFR-TKIs have been identified, such as original or induced T790M hot spot mutation, human epidermal growth factor receptor 2 (HER2) amplification, activated secondary signaling such as MET amplification or phosphatidylinositol-3 kinase (PI3K) mutation, and conversion from NSCLC to SCLC or conferred epithelial to mesenchymal transition (EMT)., Nevertheless, combined applications of EGFR-TKIs with chemotherapies brought about higher occurrence of adverse effects, rather than the expected benefit of extending the overall survival of the treated objects. Therefore, it is necessary to get deep insight into updated resistant mechanism for developing new strategies or agents to overcome EGFR-TKIs resistance and it is critical to prolong the survival of patients with NSCLC.
| > Epidermal Growth Factor Receptor-T790m Mutation|| |
EGFR inhibitors, such as erlotinib, gefitinib, and afatinib, exhibited high objective response rates and increased overall survival of NSCLC patients with oncogenic EGFR mutation (i.e., exon 19 deletions or exon 21 L858R single-point mutation)., However, despite an initial dramatic response to TKIs, patients become resistant upon the continuous treatment. Lots of evidence indicate that more than half of the EGFR-TKI resistance is caused by a secondary T790M (Thr790 → MET) mutation in the catalytic cleft of the EGFR tyrosine kinase domain., Previous structural modeling analysis of the erlotinib-bound EGFR model showed that this threonine residue was critical for the binding of erlotinib to EGFR and methionine substitution caused steric hindrance, which interfered with drug-receptor binding. Other evidence suggests that this modification disturbs the proper binding of the drug to the adenosine triphosphate (ATP) pocket of EGFR and to restore the affinity for ATP at the level of wild-type EGFR.,
| > Human Epidermal Growth Factor Receptor 2 Mutation and Amplification|| |
HER2/neu (ErbB2), EGFR (ErbB1), HER3 (ErbB3), and HER4 (ErbB4) belong to the ErbB receptor tyrosine kinase (RTK) family, which present an attractive option for targeted therapy in patients with NSCLC according to the oncogenic mutation patterns of EGFR and HER2.,, HER2 with an in-frame YVMA insertion at residue 776 is the most common abnormality detected in a survey of 96 unselected NSCLC specimens. Cancer cells expressing HER2YVMA exhibited resistance to the EGFR-TKIs such as erlotinib and gefitinib, but they remained sensitive to direct HER2 inhibitors. Highly expressed EGFR and/or HER2 have been associated with poor prognosis. Increased EGFR or HER2 gene copy numbers had a tendency to be associated with short survival in NSCLC., Through the study of preclinical in vitro and in vivo models as well as human tissues, researchers have identified that HER2 overexpression confers resistance to EGFR-TKIs in cell line models, and HER2 is amplified in both murine and human tumors with acquired resistance to erlotinib. Findings of those researchers indicate that HER2 amplification serves as a new mechanism of acquired resistance to EGFR-TKIs in EGFR-mutant NSCLC tumors, occurring independently of the EGFR T790M secondary mutation.
| > MET Amplification|| |
As a hepatocyte growth factor (HGF) receptor, MET is a RTK. Lots of evidence point to MET as a key oncogenic driver in several human cancers including small cell (SCLC) and NSCLC. Another report nominated amplifications in MET as one of the driver events specifically in otherwise oncogene-negative lung adenocarcinomas. Activation of MET-HGF pathway has been reported as one of the most critical events responsible for acquired anti-EGFR therapy resistance, and patients with increased MET gene copy numbers showed poor prognosis and resistance to EGFR-TKIs.,, It has been reported that MET amplification results in gefitinib resistance in lung cancer by activating ErbB3 signaling. Some data showed that about 20% of patients with acquired resistance to EGFR inhibition therapy harbor MET amplification. A previous report showed that MET amplification is one potential mechanism of resistance to third-generation EGFR-TKIs identified by FISH. The MET amplification accounts for approximately 5% of mechanism of resistance to first-generation EGFR-TKIs. Recent report shows that high-level MET amplification is identified as a resistance mechanism to osimertinib (AZD9291) which parallels mechanisms of acquired resistance to first-generation EGFR-TKIs. Another report also confirms that MET amplification and protein hyperactivation is a resistance mechanism to both first- and third-generation EGFR-TKIs, suggesting that MET inhibition is a possible strategy to overcome resistance of certain EGFR-mutated NSCLCs with MET amplification to AZD9291.
| > PIK3CA Mutation|| |
The ErbB family members are transmembrane RTKs, and their network activation leads to receptor autophosphorylation in C-terminal tyrosine and the recruitment to these sites of cytoplasmic signal transducers which include PLC-γ1, Ras/Raf/MEK/MAPKs, PI3K/Akt/ribosomal S6 kinase, Src, stress-activated protein kinases, PAK/JNKK/JNK, and the signal transducers and activators of transcription. PI3K pathway oncogenic activation can occur in several ways as follows: (1) mutation or amplification of gene encoding including RTKs (EGFR and HER2), subunits of PI3K (p110alfa, p110beta, p85alfa, and p85beta) and Akt; (2) activating isoform of Ras; (3) mutations, deletions, loss of functions, or epigenetic silencing of PTEN. PI3K mutations were found in about 4% of squamous cell carcinoma and 2.7% of adenocarcinoma. PI3K mutation can coexist with EGFR mutation or KRAS mutation in adenocarcinoma lung cancer. Some previous data show that in a gefitinib-resistant NSCLC cell line, continued activation of PI3K signaling by the PIK3CA oncogenic mutant, p110alpha E545K, was sufficient to abrogate gefitinib-induced apoptosis. Another group observed 5% patients with acquired PIK3CA mutations in EGFR-TKI-resistant NSCLC patients with mutant EGFR. A study in vitro identified that loss of PTEN involved in resistance to EGFR-TKIs. Some investigations confirm that PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer through activating Akt and EGFR. Some PI3K inhibitors are in progress, and several recently completed trials were leaded with PI3K inhibitor as single agent or in association with chemotherapy or other agents.
| > Epidermal Growth Factor Receptor Exon 18–25 Kinase Domain Duplication|| |
Mutations occurring as either small in-frame deletions in exon 19 or point mutations in exon 21 (L858R) usually confer sensitivity to EGFR-TKIs. ALK and ROS1 gene rearrangements have similarly allowed for the rational treatment for NSCLC. However, despite these significant advances in defining clinically relevant molecular cohorts of lung cancer, the currently identified genomic alterations account for only 50%–60% of all tumors. Recently, one targeted next-generation sequencing-based genomic profiling has first demonstrated a novel in-frame tandem duplication of EGFR exons 18–25 kinase domain duplication (EGFR-KDD). Although the index patient treated with the EGFR inhibitor afatinib experienced marked improvement and significantly decreased-tumor burden, the patient's tumor harbored an increase in the copy number of the EGFR-KDD upon disease progression. For the first time, EGFR-KDD is identified as an oncogenic and therapeutically actionable alteration through analysis of a large set of annotated lung, brain, and soft-tissue tumors and cancer cell models.
| > Noncoding RNA|| |
Long noncoding RNAs (lncRNAs) are transcripts of longer than 200 nucleotides with no protein coding function. Various studies have indicated that lncRNAs, including UCA1, HOTAIR, H19, CUDR, AK126698, and MALAT1, are associated with chemotherapy and/or EGFR-TKI resistance.,,,, A report manifests that some lncRNAs, including lncRNA BC087858, are upregulated in gefitinib-resistant cells. Further investigation shows that lncRNA BC087858 can induce acquired resistance to EGFR-TKIs by activating PI3K/Akt/ERK pathway and EMT in EGFR-mutant NSCLC.
MicroRNAs (miRNAs) as a small noncoding RNAs family of 19–24 nucleotides are involved in a variety of biological processes by regulating the expression of target genes. miR-134, miR-487b, and miR-23a were found to promote gefitinib resistance., miR-21 is able to generate gefitinib resistance through activating ALK and ERK and suppressing PTEN in NSCLC., miR-30b and miR-30c induced by EGFR and MET promote gefitinib resistance through inhibiting Bim. Similarly, miR-221 and miR-222 also increased by EGFR and MET enhance gefitinib resistance through inhibiting apoptotic peptidase activating factor-1. miRNAs are able to involve in drug resistance in positive and negative manners. Inhibition of miRNAs that promote drug resistance and enhancement of miRNAs that reverse drug resistance may provide novel prospect for combined targeted treatments in NSCLC.
| > Epithelial to Mesenchymal Transition|| |
EMT signifies reversion of epithelial phenotype and acquisition of mesenchymal characteristics, accompanied with a biological progression consisting of reversible events. Previous study shows that EMT is a determinant of sensitivity of NSCLC cell lines and xenografts to EGFR-TKIs. Another investigation demonstrates that EMT markers are increased in patients with NSCLC showing resistance to cisplatin-based chemoradiotherapy. EMT induction in vitro makes NSCLC cells with EGFR mutations less sensitive to EGFR-TKIs.,, Recent evidence shows that EMT can contribute to drug resistance in several carcinomas such as pancreatic cancer and lung cancer., The acquisition or reversion of EMT was consistent with the changes in drug sensitivity. EGFR-mutant NSCLC cells exhibit a decreased sensitivity to gefitinib when an EMT phenotype is induced by transforming growth factor (TGF), HGF, or interleukin 6.,, Sensitivity to cisplatin is decreased in NSCLC cells for EMT induction by TGF, and sensitivity to etoposide is less in SCLC cells with an HGF-induced EMT., New therapeutic strategies of reverting EMT might be used for overcoming resistance to chemotherapy and/or targeted therapy.
| > Conversion of Nonsmall Cell Lung Cancer to Small Cell Lung Cancer|| |
Some studies showed that after an initial response to EGFR-TKIs, EGFR-mutated adenocarcinoma is transformed to SCLC and a similar activating mutation is confirmed by EGFR mutation analysis in both original lung adenocarcinoma and metastatic SCLC of these patients., Other case describes that EGFR-mutant metastatic adenocarcinoma is transformed into SCLC after developing resistance in a never-smoking female. An investigation manifests that after developing clinical resistance to EGFR-TKI, a pretreatment adenocarcinoma is transformed into a combined SCLC-adenocarcinoma in one patient and four patients have EGFR-mutant SCLC or mixed histology tumors. The finding that the same EGFR-mutant cancer can manifest both as an adenocarcinoma and as a SCLC hints at the existence of a pluripotent population of EGFR-mutant cancer cells or cancer stem cells that are the source of resistance. SCLC histology has been found in 3%–14% of patients with acquired resistance to EGFR-TKIs. A high frequency of conversion of NSCLC to SCLC, together with marked EGFR amplification, PIK3CA mutations, EMT, and the loss of genetic resistance mechanisms are observed in the absence of continuous TKI treatment.
| > Prospective Strategies or Agents to Overcome Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance in Epidermal Growth Factor Receptor-Mutant Nonsmall Cell Lung Cancer|| |
Although EGFR inhibitors for NSCLC treatment have been applied in clinical practices with great success, their clinical benefits were somewhat hampered by the rising acquired resistance. New generation inhibitors or combination drug therapy could be effective strategies to cope with the challenge.
New generation inhibitors
Acquired resistances after treatment with first-generation EGFR-TKIs lead researchers to develop second-generation EGFR-TKIs, in which afatinib has progressed furthest in clinical development and has been approved by NICE as an option for first-line EGFR-TKI therapy. Dacomitinib and three other compounds including pelitinib, canertinib, and ceratinib were investigated but are no longer in development for patients with NSCLC for disappointing clinical results.
Third-generation inhibitors are in development, of which AZD9291 and rociletinib have the furthest progression in clinic. To solve resistance caused by T790M mutation, new inhibitors with irreversible binding to the ATP pocket of EGFR and the selective targeting of T790M-harboring receptors have been developed.,, A mono-anilino-pyrimidine compound AZD9291, as a novel and irreversible EGFR-TKI, has proved to be more effective against both EGFR-TKI sensitizing and resistant T790M mutation in preclinical models and Phase 1 clinical study. Although new irreversible inhibitors are more potent than gefitinib against T790M, more studies are needed for the efficacy and safety of these new generation EGFR-TKIs in the Phase 3 clinical trials. Rociletinib is a potent irreversible inhibitor of sensitizing EGFR mutations and T790M-resistant mutations. Rociletinib is in Phase 2 and 3 studies. For HM61713, an irreversible mutant-selective EGFR inhibitor that is wild-type sparing, an expansion cohort at increased dose is planned.
As one of the third-generation irreversible EGFR-TKIs, osimertinib can specifically target common activating EGFR mutations − exon19 deletion and L858R and the T790M resistance mutation. The mutation at the cysteine (C797) residue that osimertinib binds to lead to its resistance., For the current available first- and second-generation EGFR-TKIs can inhibit this C797S mutation in vitro, a combination of first- and third-generation EGFR-TKIs has been proposed as a therapeutic strategy to overcome the C797S/T790M mutations if the mutations occur in separate allele of the chromosome.
Combination of epidermal growth factor receptor with MET blockade
Several combination strategies are being investigated, but results are preliminary and immature. One of the strategies is combination of MET inhibitors such as MET inhibitors, such as cabozantinib, tivantinib, and INC280. Although many new MET inhibition compounds including antibody inhibition, small-molecule inhibitors, and others have entered clinical trials, the frequency of MET amplification in NSCLC ranges from 3% to 10%, depending on the detection technique, cutoff criteria, and selection of samples. Preclinical data demonstrated that combination of afatinib with cetuximab (EGFR-targeting antibody) resulted in tumor response in erlotinib-resistant tumor xenografts, and the combination efficacy will be investigated by a Phase 2/3 trial., Other combined inhibitor therapies including PI3K inhibitor (buparlisib), heat shock protein 90 inhibitor (AUY922), or JAK inhibitor (ruxolitinib) are in clinical development.
Combined targeting of epidermal growth factor receptor and pyruvate dehydrogenase kinase
Glycolysis, as a predominant process for most cancer cells to utilize glucose, is involved in cancer development. Targeting critical glycolysis enzymes, such as pyruvate dehydrogenase kinase (PDK), might be a promising approach to work alone or in combination with other treatments for cancer therapy. As a widely regarded PDK inhibitor, dichloroacetate (DCA) attenuates cancer progression in many cancers. Previously, several combinations of DCA with platinum-based drug for NSCLC treatment have been reported and majority of them were focused on the classical cytotoxic chemotherapy., Recent report has showed that combination of erlotinib and gefitinib with DCA exerts synergistic effects in an EGFR-mutant NSCLC.
Combination treatment of epidermal growth factor receptor-tyrosine kinase inhibitor and Bcl-2 inhibitors
Overexpression of anti-apoptotic Bcl-2 family members (i.e., Bcl-2, Bcl-XL, and Mcl-1) and dysregulation of proapoptotic family members (i.e., Bad, Bim, Bax, Bak, etc.) are involved in the mediation of chemo- or radio-resistance in human lung cancers, indicating that Bcl-2 family members have the potential to be critical targets for lung cancer treatment. An investigation revealed that Bcl-2 knockdown induced by small interfering could reverse acquired T790M mutation in EGFR-TKIs-resistant H1975 cell line. The members of Bcl-2 family own four conserved Bcl-2 homology (BH) domains: BH1, BH2, BH3, and BH4. The BH3 mimetic agents could bind to the hydrophobic cleft of Bcl-2/Bcl-XL to act as competitive inhibitors., Gossypol (AT-101), a pan-Bcl-2 inhibitor, has shown antitumor effect in several cancer cell lines.,, Recent study has revealed that AT-101 enhances gefitinib sensitivity in NSCLC with EGFR T790M mutations and the combined treatment with AT-101 and gefitinib induced additional cell death in vitro and in vivo. Although four Bcl-2 inhibitors, oblimersen sodium (G3139), gossypol (AT-101), obatoclax (GX15-070), and ABT-263, have already been tested in human clinical trials, they showed limited clinical efficacy., The BH4 domain is required for the survival activity of Bcl-2, and its removal can convert Bcl-2 from a survival to a killer molecule. BDA-366, a small-molecule Bcl-2-BH4 domain antagonist, is recently identified and exhibits potent efficacy against human lung cancer.
PD-1 pathway activation contributes to immune evasion in EGFR-driven lung cancers. Phase 1 trials combining EGFR-TKIs with immunotherapies are ongoing, including several anti-PD-1 monoclonal antibody (nivolumab, pembrolizumab, and MPDL3280A). Nivolumab, a fully human IgG4 immune checkpoint inhibitory antibody, could bind to PD-1, preventing its interaction with its ligands PD-L1 and PD-L2., In different cancer types, tumor infiltrating lymphocytes have been found to express PD-1, while the upregulation of PD-L1 by tumor cells has been interpreted as a possible mechanism of resistance of the tumor to the host immune response., Nivolumab has been approved in the US and Europe as second-line treatment for advanced NSCLC.
An improved understanding of the mechanisms of acquired EGFR-TKI resistance and treatment strategies that are rationally tailored to them drives the treatment into a new exciting phase in NSCLC. These findings will provide a new concept for the development of novel therapeutic approaches in the treatment of refractory and relapsed patients who are no longer sensitive to EGFR-TKIs. In the future, the co-treatment strategy or new generation inhibitor in the clinical setting remains to be further clarified.
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Conflicts of interest
There are no conflicts of interest.
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