T790M and acquired resistance of EGFR TKI: a literature review of clinical reports

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib are promising therapies for patients with advanced non-small-cell lung cancer (NSCLC). Patients with somatic activating mutations in the EGFR gene have dramatic response initially, but would eventually develop resistance to these TKIs. Subsequent studies found that a secondary mutation in the EGFR gene (T790M mutation) and amplification of the MET proto-oncogene could be the main resistance mechanisms involved. The current review is focused on T790M, which is thought to cause steric hindrance and impair the binding of gefitinib/erlotinib. The T790M is present as a minor allele before TKI therapy and accounts for about half of the acquired resistant cases. Conflicting results were reported for gefitinib-resistant, T790M-acquired patients who had switched to erlotinib treatment, which was proposed to be efficacious. The switch therapy was presumed to work for EGFR wild type patients and previously gefitinib responding patients. MET amplification accounts for about 20% of TKI acquired-resistant patients by a different molecular pathway from T790M; some of these patients will also concurrently have T790M mutation and might still not respond to irreversible TKI. As for the detection of T790M, polymerase chain reaction (PCR), especially mutant-enriched PCR was found to be more sensitive than direct DNA sequencing. In addition, whole genome amplification might also be useful and can be incorporated with future noninvasive method for detecting T790M. A better understanding of the mechanisms leading to TKI resistance is crucial in the development of effective treatment and the design of future clinical studies.     

Acquired resistance of non-small cell lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors

Activation of epidermal growth factor receptor (EGFR) triggers anti-apoptotic signaling, proliferation, angiogenesis, invasion, metastasis, and drug resistance, which leads to development and progression of human epithelial cancers, including non-small cell lung cancer (NSCLC). Inhibition of EGFR by tyrosine kinase inhibitors such as gefitinib and erlotinib has provided a new hope for the cure of NSCLC patients. However, acquired resistance to gefitinib and erlotinib via EGFR-mutant NSCLC has occurred through various molecular mechanisms such as T790M secondary mutation, MET amplification, hepatocyte growth factor (HGF) overexpression, PTEN downregulation, epithelial-mesenchymal transition (EMT), and other mechanisms. This review will discuss the biology of receptor tyrosine kinase inhibition and focus on the molecular mechanisms of acquired resistance to tyrosine kinase inhibitors of EGFR-mutant NSCLC.     

The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP

Lung cancers caused by activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to small molecule tyrosine kinase inhibitors (TKIs), but the efficacy of these agents is often limited because of the emergence of drug resistance conferred by a second mutation, T790M. Threonine 790 is the “gatekeeper” residue, an important determinant of inhibitor specificity in the ATP binding pocket. The T790M mutation has been thought to cause resistance by sterically blocking binding of TKIs such as gefitinib and erlotinib, but this explanation is difficult to reconcile with the fact that it remains sensitive to structurally similar irreversible inhibitors. Here, we show by using a direct binding assay that T790M mutants retain low-nanomolar affinity for gefitinib. Furthermore, we show that the T790M mutation activates WT EGFR and that introduction of the T790M mutation increases the ATP affinity of the oncogenic L858R mutant by more than an order of magnitude. The increased ATP affinity is the primary mechanism by which the T790M mutation confers drug resistance. Crystallographic analysis of the T790M mutant shows how it can adapt to accommodate tight binding of diverse inhibitors, including the irreversible inhibitor HKI-272, and also suggests a structural mechanism for catalytic activation. We conclude that the T790M mutation is a “generic” resistance mutation that will reduce the potency of any ATP-competitive kinase inhibitor and that irreversible inhibitors overcome this resistance simply through covalent binding, not as a result of an alternative binding mode.     

Molecular imaging of active mutant L858R EGF receptor (EGFR) kinase-expressing nonsmall cell lung carcinomas using PET/CT

The importance of the EGF receptor (EGFR) signaling pathway in the development and progression of nonsmall cell lung carcinomas (NSCLC) is widely recognized. Gene sequencing studies revealed that a majority of tumors responding to EGFR kinase inhibitors harbor activating mutations in the EGFR kinase domain. This underscores the need for novel biomarkers and diagnostic imaging approaches to identify patients who may benefit from particular therapeutic agents and approaches with improved efficacy and safety profiles. To this goal, we developed 4-[(3-iodophenyl)amino]-7-{2-[2-{2-(2-[2-{2-([(18)F]fluoroethoxy)-ethoxy}-ethoxy]-ethoxy)-ethoxy}-ethoxy]-quinazoline-6-yl-acrylamide ([(18)F]F-PEG6-IPQA), a radiotracer with increased selectivity and irreversible binding to the active mutant L858R EGFR kinase. We show that PET with [(18)F]F-PEG6-IPQA in tumor-bearing mice discriminates H3255 NSCLC xenografts expressing L858R mutant EGFR from H441 and PC14 xenografts expressing EGFR or H1975 xenografts with L858R/T790M dual mutation in EGFR kinase domain, which confers resistance to EGFR inhibitors (i.e., gefitinib). The T790M mutation precludes the [(18)F]F-PEG6-IPQA from irreversible binding to EGFR. These results suggest that PET with [(18)F]F-PEG6-IPQA could be used for the selection of NSCLC patients for individualized therapy with small molecular inhibitors of EGFR kinase that are currently used in the clinic and have a similar structure (i.e., iressa, gefitinib, and erlotinib).     

MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib

In human lung adenocarcinomas harboring EGFR mutations, a second-site point mutation that substitutes methionine for threonine at position 790 (T790M) is associated with approximately half of cases of acquired resistance to the EGFR kinase inhibitors, gefitinib and erlotinib. To identify other potential mechanisms that contribute to disease progression, we used array-based comparative genomic hybridization (aCGH) to compare genomic profiles of EGFR mutant tumors from untreated patients with those from patients with acquired resistance. Among three loci demonstrating recurrent copy number alterations (CNAs) specific to the acquired resistance set, one contained the MET proto-oncogene. Collectively, analysis of tumor samples from multiple independent patient cohorts revealed that MET was amplified in tumors from 9 of 43 (21%) patients with acquired resistance but in only two tumors from 62 untreated patients (3%) (P = 0.007, Fisher's Exact test). Among 10 resistant tumors from the nine patients with MET amplification, 4 also harbored the EGFR^T790M mutation. We also found that an existing EGFR mutant lung adenocarcinoma cell line, NCI-H820, harbors MET amplification in addition to a drug-sensitive EGFR mutation and the T790M change. Growth inhibition studies demonstrate that these cells are resistant to both erlotinib and an irreversible EGFR inhibitor (CL-387,785) but sensitive to a multikinase inhibitor (XL880) with potent activity against MET. Taken together, these data suggest that MET amplification occurs independently of EGFR^T790M mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to gefitinib or erlotinib.     

Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): a better mousetrap? A review of the clinical evidence

The discovery of activating epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) in 2004 heralded the era of molecular targeted therapy in NSCLC. First-generation small molecule, reversible tyrosine kinase inhibitors (TKIs) of EGFR, gefitinib and erlotinib, had been approved for second- or third-line treatment of NSCLC prior to the knowledge of these mutations. However, resistance to gefitinib and erlotinib invariably develops after prolonged clinical use. Two second-generation irreversible EGFR TKIs, afatinib (BIBW 2992) and dacomitinib (PF-00299804), that can potentially overcome the majority of these resistances are in late stage clinical development. Here I will review the clinical data of EGFR TKIs and discuss the appropriate future role of afatinib and dacomitinib in NSCLC: whether as replacement of erlotinib or gefitinib or only after erlotinib or gefitinib failure and whether different subgroups would benefit from different approaches.     

Therapeutic strategy for advanced EGFR mutant non-small-cell lung carcinoma

Activating mutation in exons 19 or 21 of epidermal growth factor receptor (EGFR) in non-small-cell lung cancers (NSCLC) are associated with increased sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib. Cancer patients harboring activating EGFR mutations benefit from first-line TKI therapy. Yet 10% of patients present a primary TKI resistance, while 50% of the others develop a secondary resistance within 9–12 months after starting TKI. The RECIST's definition of progression appears flawed when applied to EGFR-mutated NSCLC patients. Most often, tumor volume shrinking widely exceeds 30% during TKI response and kinetics of growth is low during relapse. At present, secondary resistance mechanisms associated with progression are better known: clonal selection of EGFR resistance mutation (T790M mutation in exon 20), amplification of transmembrane receptors for other growth factors (c-met, HER family, IGF1R, or AXL), downstream molecular alterations in EGFR signaling pathway (PI3K or PTEN), and epithelial–mesenchymal transition or transdifferentiation to small-cell cancer. The best strategy for secondary resistance is not well-defined: maintaining TKI therapy, switching to chemotherapy, combining both treatments, or using new therapies targeting other signaling pathways.     

Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors

The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC). Dramatic and durable responses have occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In contrast, these inhibitors have shown limited efficacy in glioblastoma, where a distinct EGFR mutation, the variant III (vIII) in-frame deletion of exons 2-7, is commonly found. In this study, we determined that EGFRvIII mutation was present in 5% (3/56) of analyzed human lung squamous cell carcinoma (SCC) but was not present in human lung adenocarcinoma (0/123). We analyzed the role of the EGFRvIII mutation in lung tumorigenesis and its response to tyrosine kinase inhibition. Tissue-specific expression of EGFRvIII in the murine lung led to the development of NSCLC. Most importantly, these lung tumors depend on EGFRvIII expression for maintenance. Treatment with an irreversible EGFR inhibitor, HKI-272, dramatically reduced the size of these EGFRvIII-driven murine tumors in 1 week. Similarly, Ba/F3 cells transformed with the EGFRvIII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272. These findings suggest a therapeutic strategy for cancers harboring the EGFRvIII mutation.     

Combined Erlotinib and Cetuximab overcome the acquired resistance to epidermal growth factor receptors tyrosine kinase inhibitor in non-small-cell lung cancer

Purpose

Non-small-cell lung cancer (NSCLC) cells with somatic mutations in epidermal growth factor receptors (EGFR) are initially susceptible to tyrosine kinase inhibitor (TKI); however, eventually resistance to TKI is developed in these cells, which leads to the failure of treatment. The most common mechanism of this acquired drug resistance is development of a secondary T790M mutation in EGFR. In this study, we investigated the effects of the combination of Erlotinib and Cetuximab on T790M and L858R mutation lung cancer cells lines (H1975), in the primary NSCLC cells with the T790M mutation and TKI-resistant EGFR mutations human tumor xenograft model (H1975).

Methods

The effects of these two agents on cell proliferation, apoptosis, and EGFR-dependent signaling were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, annexin V staining, and Western blotting. Sensitivity of EGFR inhibitors was detected in the primary tumor cell suspension and human tumor xenograft model (H1975).

Results

Compared with single-agent treatment, the combination of Cetuximab and Erlotinib increased apoptosis of EGFR TKI–resistant NSCLC cells (H1975), resulting in more pronounced growth inhibition on cell proliferation and significant inhibition of EGFR-dependent signaling.

Conclusions

These data suggest that treatment with a combination of Erlotinib and Cetuximab overcomes T790M-mediated drug resistance.     

一代EGFR-TKIs治疗后进展的晚期NSCLC外周血T790M突变特征

目的探究真实世界中表皮生长因子受体(EGFR)敏感突变的晚期NSCLC患者使用吉非替尼、厄洛替尼、埃克替尼一线治疗进展后T790M突变的分布特征。 方法2017年6月至2019年6月期间557例肺癌患者,145例经病理组织学或细胞学确诊为晚期非小细胞肺癌(NSCLC)且具有EGFR敏感突变的患者,给予吉非替尼、厄洛替尼、埃克替尼一线治疗。随访进展后,采集其外周血10 ml,利用Super-ARMS法检测T790M突变。通过χ²检验,Kaplan-Meier分析,回顾性分析晚期NSCLC患者接受吉非替尼、厄洛替尼、埃克替尼一线治疗后T790M突变患者的分布特征。 结果回顾性分析的145例患者,56例一线接受吉非替尼治疗,16例接受厄洛替尼治疗,73例接受埃克替尼治疗。Super-ARMS检测结果显示,一代EGFR-TKIs治疗进展后T790M突变的总体发生率为40% (58/145),其中吉非替尼组41.07% (23/56)、厄洛替尼组31.25%(5/16)、埃克替尼组41.10% (30/73)。三组患者之间T790M突变的发生率无统计学差异。但是,肺腺癌(P＝0.0001)及初始EGFR突变为19del(P＝0.0014)的患者更易发生T790M突变。T790M阳性患者中,吉非替尼、厄洛替尼、埃克替尼的中位PFS(mPFS)分别为：11个月、18个月和12个月,组间无统计学差异。TKI治疗1年、2年后T790M突变率及T790M阳性人群的中位PFS均无统计学差异。 结论真实世界中吉非替尼、厄洛替尼、埃克替尼一线治疗晚期NSCLC耐药进展后,其血检标本T790M的突变发生率无统计学差异。但是,初始突变为19del的患者相较于L858R突变的患者更容易发生T790M突变。这也进一步预示着NSCLC患者精细化管理的必要性。     

Dramatic response to osimertinib combined with crizotinib in EGFR T790 M mutation only in blood and Met amplification only in tumor tissue expressive non-small cell lung cancer: A case report

Rationale:Besides the T790 M mutation, it may coexist with bypass pathway activation in real clinical cases for patients with EGFR mutations who resisted to the first- and second-generation tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). There are limited clinical trial data describing the efficacy of osimertinib combined with MET inhibition in EGFR T790M-mutant NSCLC patients with Met amplification.Patient concerns:A non-smoking 53-year-old male patient with lung adenocarcinoma underwent gefitinib, afatinib, and osimertinib combined with crizotinib treatment and developed different EGFR resistance mutations.Diagnoses:The patient was diagnosed with lung adenocarcinoma (stage cT4N2M0, IIIB). After resistance to the therapy targeting EGFR exon 21 L858R point mutation, T790 M mutation was detected in liquid biopsy and Met amplification was detected via tissue biopsy by next-generation sequencing (NGS).Interventions:The patient received systemic treatments, including chemotherapy, gefitinib, afatinib, and osimertinib combined with crizotinib.Outcomes:The patient died of multisystem organ failure and had an overall survival of 24 months.Lessons:Although osimertinib combined with crizotinib therapy showed dramatic tumor shrinkage in both the primary tumor and bone metastasis to an EGFR T790M-mutant NSCLC patient with MET amplification, the progression-free survival (PFS) was only two months.     

Management of patients with resistance to EGFR-TKI

Patients presenting with non-small cell lung cancer (NSCLC) and active EGFR mutation have a high response rate (60-70%) to EGFR tyrosine kinase inhibitors (TKI) with little immediate progression (primary resistance). However, progression on this treatment (secondary resistance) is inevitable even for those who responded initially. These two situations are distinct in terms of management. In case of primary resistance, screening for other associated molecular abnormalities (tumour heterogeneity) should be done, even resulting in a false positive in the initial screening of EGFR mutation. In case of secondary resistance, a new pathology sample should be taken insofar as is possible to determine the presence of an acquired mutation of EGFR resistance (T790M in 60% of cases) or c-Met amplification (20% of cases). The presence of a T790M mutation could respond to irreversible EGFR-TKI, while a c-Met amplification could be managed with a targeted anti-Met therapy. However, the gold standard is still cytotoxic chemotherapy at present if a clinical trial based on a targeted therapy is not possible.     

The role of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of advanced stage non-small cell lung cancer

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) like erlotinib and gefitinib have been extensively studied. Multiple randomized trials have evaluated the role of EGFR TKIs in advanced stage non-small cell lung cancer (NSCLC) as a monotherapy in the first line, or subsequent lines of therapy, and in the first line in the maintenance setting or in combination with chemotherapy. Most of these trials showed positive results in particular for selected patients with specific clinical characteristic and somatic activating mutation of EGFR. A further understanding of the mechanism of primary and secondary resistance has led to the development of promising novel agents designed to overcome resistance to EGFR.     

A simple view on lung cancer biology: The EGFR pathway

Epidermal growth factor receptor (EGFR) is a cell membrane tyrosine kinase receptor. Activating mutations at exon 19?and 21?of the EGFR gene are associated with the occurrence and development of lung adenocarcinoma. These gain of function mutations predict responsiveness to EGFR tyrosine kinase inhibitors (TKis), erlotinib or gefitinib and are also a favorable prognostic factor in lung cancer. Sequencing is the recommended technique to detect the mutations, but other more sensitive technics are under evaluation. Treatment as first line therapy by gefitinib is limited to lung cancer patients harboring an EGFR mutation. Erlotinib can be given regardless of the EGFR status as second or third line therapy, as well as maintenance therapy in patients with a stable disease after platinum based chemotherapy. In EGFR mutated tumors, most patients present a recurrence of the disease, despite an initial response on EGFR TKis. Two mechanisms of secondary resistance have been identified, the selection of the T790M mutation in EGFR exon 20?and the MET amplification. Other molecular anomalies as the ras mutations or the EMLA-ALK protein fusion are mutually exclusive with the EGFR mutations and are associated with primary resistance to EGFR TKis.     

Epidermal growth factor receptor mutations and susceptibility to targeted therapy in lung cancer

According to 2002 estimates, 1.35 million people were diagnosed with and 1.18 million died of lung cancer worldwide. Recently, a new class of medications targeting signal transduction pathways has come into focus in the treatment of various malignancies. In lung cancer, the molecules gefitinib and erlotinib which target the intracellular kinase domain of the epidermal growth factor receptor (EGFR), cause significant tumour responses and, in the case of erlotinib, a survival benefit in patients with previously treated cancers. Responses were most pronounced in female non-smokers with adenocarcinoma histology. These patients were found more likely to harbour mutations of the receptor kinase domain, including in-frame deletions in exon 19 (such as deletions of codons 746-750) and point deletions in exon 21 (such as L858R). Other EGFR kinase domain mutations have been found to confer resistance (T790M) or differential susceptibility to erlotinib and gefitinib (E884K). Gene amplification of EGFR also may predict sensitivity, although the mechanism by which this occurs is unclear, because level of expression detected by immunohistochemistry has not been correlated with increased sensitivity. Phenotypic and genotypic epithelial to mesenchymal transition may be an indicator of resistance to EGFR kinase inhibitors. In this article, we review efforts that have been undertaken to identify genomic determinants of drug susceptibility to EGFR tyrosine kinase inhibitors, with particular focus on the role of gene mutations.     

T790M mutation positive squamous cell carcinoma transformation from EGFR-mutated lung adenocarcinoma after low dose erlotinib: A case report and literature review

Rationale:Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely used for the treatment of EGFR mutation positive advanced nonsmall cell lung cancer (NSCLC); however, acquired resistance is known to develop during these treatments. Among these mechanisms, histological transformation is seldom encountered. Although platinum based chemotherapy has been reported to be effective in the treatment of patients with small cell lung cancer transformation, there is a lack of information on the treatment of patients with squamous cell carcinoma (SQ) transformation.Patient Concerns and Diagnosis:An 80-year-old nonsmoking woman was referred to our hospital because of an abnormal shadow on her chest radiograph. Diagnostic bronchoscopy was performed and pathological examination revealed adenocarcinoma. Mutation analysis of the EGFR gene revealed deletion of E746-A750 in exon 19. She refused both surgical treatment and radiation therapy, and preferred periodic radiologic follow-up. Unfortunately, approximately a year and a half after the initial diagnosis, the primary lesion enlarged, and many pleural nodules were newly detected (clinically T4N2M1a, stage IVA).Interventions and Outcomes:Based on EGFR mutation analysis, a reduced dose of daily erlotinib was prescribed, which achieved a partial response and 34 months of progression-free survival (PFS). A repeated biopsy with an endobronchial cryoprobe was performed on the enlarged primary lesion. Pathological examination revealed SQ harboring an identical EGFR mutation with a secondary EGFR T790M mutation. Osimertinib 80 mg once a day was started as second line therapy, which resulted in 8 months of PFS and 15 months of survival.Lesson:The literature review and our report suggest that osimertinib is a promising treatment for NSCLC regardless of histology if T790M is present as an acquired mutation.     

TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer

The epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor erlotinib has been proven to be highly effective in the treatment of nonsmall cell lung cancer (NSCLC) harboring oncogenic EGFR mutations. The majority of patients, however, will eventually develop resistance and succumb to the disease. Recent studies have identified secondary mutations in the EGFR (EGFR T790M) and amplification of the N-Methyl-N′-nitro-N-nitroso-guanidine (MNNG) HOS transforming gene (MET) oncogene as two principal mechanisms of acquired resistance. Although they can account for approximately 50% of acquired resistance cases together, in the remaining 50%, the mechanism remains unknown. In NSCLC-derived cell lines and early-stage tumors before erlotinib treatment, we have uncovered the existence of a subpopulation of cells that are intrinsically resistant to erlotinib and display features suggestive of epithelial-to-mesenchymal transition (EMT). We showed that activation of TGF-β–mediated signaling was sufficient to induce these phenotypes. In particular, we determined that an increased TGF-β–dependent IL-6 secretion unleashed previously addicted lung tumor cells from their EGFR dependency. Because IL-6 and TGF-β are prominently produced during inflammatory response, we used a mouse model system to determine whether inflammation might impair erlotinib sensitivity. Indeed, induction of inflammation not only stimulated IL-6 secretion but was sufficient to decrease the tumor response to erlotinib. Our data, thus, argue that both tumor cell-autonomous mechanisms and/or activation of the tumor microenvironment could contribute to primary and acquired erlotinib resistance, and as such, treatments based on EGFR inhibition may not be sufficient for the effective treatment of lung-cancer patients harboring mutant EGFR.     

Factors predicting response to EGFR tyrosine kinase inhibitors

Over the past few years, two epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) and erlotinib (Tarceva), have been developed for the treatment of patients with cancer. In patients with non-small cell lung cancer (NSCLC), these therapies occasionally demonstrate remarkable and durable activity. However, EGFR TKIs are active in only a small subset of patients. Responders are more often nonsmokers, of East Asian descent, and female, and have tumors with adenocarcinoma histology. In April 2004, two groups reported that a cluster of somatic mutations in the kinase domain of the EGFR are observed in the majority of NSCLCs that demonstrate remarkable responses to EGFR TKIs. These findings have been validated by other investigators and have revolutionized the manner in which clinicians are thinking about their utilization for the treatment of NSCLC. This review focuses on the clinical experience with EGFR TKIs, the present knowledge regarding the biology of EGFR mutations, the limitations of using EGFR mutational status to predict who will respond to EGFR TKIs, and the implications of this information on the use of these agents for the treatment of advanced NSCLC.     

Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases

To realize the full potential of targeted protein kinase inhibitors for the treatment of cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of BCR-ABL, KIT, and the EGF receptor (EGFR) have been found that confer resistance to the drugs imatinib, gefitinib, and erlotinib. The mutations weaken or prevent drug binding, and interestingly, one of the most common sites of mutation in all three kinases is a highly conserved "gatekeeper" threonine residue near the kinase active site. We have identified existing clinical compounds that bind and inhibit drug-resistant mutant variants of ABL, KIT, and EGFR. We found that the Aurora kinase inhibitor VX-680 and the p38 inhibitor BIRB-796 inhibit the imatinib- and BMS-354825-resistant ABL(T315I) kinase. The KIT/FLT3 inhibitor SU-11248 potently inhibits the imatinib-resistant KIT(V559D/T670I) kinase, consistent with the clinical efficacy of SU-11248 against imatinib-resistant gastrointestinal tumors, and the EGFR inhibitors EKB-569 and CI-1033, but not GW-572016 and ZD-6474, potently inhibit the gefitinib- and erlotinib-resistant EGFR(L858R/T790M) kinase. EKB-569 and CI-1033 are already in clinical trials, and our results suggest that they should be considered for testing in the treatment of gefitinib/erlotinib-resistant non-small cell lung cancer. The results highlight the strategy of screening existing clinical compounds against newly identified drug-resistant mutant variants to find compounds that may serve as starting points for the development of next-generation drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted therapy.     

Erlotinib as a salvage treatment after gefitinib failure for advanced non-small-cell lung cancer patients with brain metastasis: A successful case report and review

Rationale:The guidelines recommended gefitinib as a first-line targeted treatment for stage IV non-small-cell lung cancer (NSCLC) patients with EGFR mutations. However, resistance to gefitinib ensues invariably and there is little evidence as for the effectiveness of subsequent salvage treatment for patients without T790m mutation. The case is to evaluate the efficacy of erlotinib, another EGFR-TKI, after failed first-line use of gefitinib.Patient concerns:We described a 55-year-old man with good performance status (PS).Diagnoses:He was histopathologically diagnosed stage IV lung adenocarcinoma with EGFR mutations in November 2018.Interventions:He was administrated with gefitinib daily (250 mg) for activating epidermal growth factor receptor (EGFR) mutations (exon 19 deletions,19del), and combined with platinum-based dual-drug chemotherapy. During the target treatments, the optimal efficacy evaluation was partial remission (PR) with a 12-month progression-free survival (PFS) time. Later, the intracranial progression of the patient rendered the treatment change to erlotinib.Outcomes:It is surprising that the tumor lesion in brain as well as lung relieved obviously. His progression-free survival (PFS)was nearly 11 months, and the overall survival (OS)was>36 months up to now. The adverse events were tolerable.Lessions:This case manifests that re-biopsy of advanced or recurrent NSCLC is beneficial to make a better therapeutic regimen, and erlotinib can be used as a salvage treatment after gefitinib failure.