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Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy

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Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy cells Review Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy Tatsuya Nagano * , Motoko Tachihara and Yoshihiro Nishimura Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; [email protected] (M.T.); [email protected] (Y.N.) * Correspondence: [email protected]; Tel.: +81-78-382-5660 Received: 25 October 2018; Accepted: 15 November 2018; Published: 15 November 2018 Abstract: Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improves the overall survival of patients with EGFR-mutated non-small-cell lung cancer (NSCLC). First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) or second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) are effective for the treatment of EGFR-mutated NSCLC, especially in patients with EGFR exon 19 deletions or an exon 21 L858R mutation. However, almost all cases experience disease recurrence after 1 to 2 years due to acquired resistance. The EGFR T790M mutation in exon 20 is the most frequent alteration associated with the development of acquired resistance. Osimertinib—a third-generation EGFR-TKI—targets the T790M mutation and has demonstrated high efficacy against EGFR-mutated lung cancer. However, the development of acquired resistance to third-generation EGFR-TKI, involving the cysteine residue at codon 797 mutation, has been observed. Other mechanisms of acquired resistance include the activation of alternative pathways or downstream targets and histological transformation (i.e., epithelial–mesenchymal transition or conversion to small-cell lung cancer). Furthermore, the development of primary resistance through overexpression of the hepatocyte growth factor and suppression of Bcl-2-like protein 11 expression may lead to problems. In this report, we review these mechanisms and discuss therapeutic strategies to overcome resistance to EGFR-TKIs. Keywords: acquired resistance; T790M; C797S; alternative pathway; transformation; primary resistance 1. Introduction The epidermal growth factor receptor (EGFR) is a receptor protein penetrating the cell membrane. The kinase domain is composed of the N and C lobes and an adenosine triphosphate (ATP) binding cleft between the two lobes. Following the binding of a ligand to the receptor, an asymmetric dimer is formed and the phosphate of ATP is transferred to the tyrosine residue of the regulatory domain. Various proteins are bound to this phosphorylated tyrosine and signals are transmitted downstream through the rat sarcoma (RAS)-rapidly accelerated fibrosarcoma (RAF)-mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB, also known as AKT) pathways. EGFR tyrosine kinase inhibitors (TKIs) competitively inhibit ATP with cleft of the kinase domain. Gefitinib, a first-generation EGFR-TKI, greatly improved the prognosis of EGFR gene mutation-positive patients with non-small-cell lung cancer (NSCLC) [1,2]. The vast majority (93%) of EGFR activation mutations (common mutations) occur in exons 19 to 21. In addition, deletion mutations in exon 19 and L858R mutations in exon 21 are particularly frequent (44.8% and 39.8%, respectively) [3]. Although EGFR-TKIs show an excellent therapeutic effect on EGFR-mutated NSCLC, Cells 2018, 7, 212; doi:10.3390/cells7110212 www.mdpi.com/journal/cells Cells 2018, 7, x FOR PEER REVIEW 2 of 17 Cells 2018, 7, 212 2 of 16 particularly frequent (44.8% and 39.8%, respectively) [3]. Although EGFR-TKIs show an excellent therapeutic effect on EGFR-mutated NSCLC, most cancers develop resistance to EGFR-TKI. The most cancersT790M developmutation resistance in exon 20 tois recognized EGFR-TKI. in The approximately T790M mutation half of in EGFR-TKI exon 20 istolerance recognized cases in [4,5]. In approximatelythis review, halfof we EGFR-TKI will summariz tolerancee casesthe mechanism [4,5]. In this of review, EGFR-TKI we will tolerance summarize and the present mechanism treatment of EGFR-TKIstrategies tolerance to overcome and present resistance. treatment There are strategies several to outstanding overcome resistance.reviews so far There [6–9], are but several therapeutic outstandingdrugs reviews progress so one far [ 6after–9], butanother therapeutic and a drugsnew resistance progress onemechanism after another emerges. and a Therefore, new resistance we would mechanismlike to emerges. review Therefore, focusing weon would the novel like to acquired review focusing resistance on theof novelthe third-generation acquired resistance EGFR-TKI, of the third-generationosimertinib based EGFR-TKI, on the latest osimertinib academic based information. on the latest academic information. 2. Acquired2. Acquired Resistance Resistance 2.1. T790M2.1. T790M “Gatekeeper” “Gatekeeper” Mutation Mutation DespiteDespite the initial the responseinitial response to first-generation to first-generation EGFR-TKIs, EGFR-TKIs, patients patients with NSCLCs with NSCLCs harboring harboring EGFR mutationsEGFR mutations acquire acquire resistance resistance to these to these agents, agents, with with a median a median time time to disease to disease progression progression of of approximatelyapproximately 12 months12 months [10– 14[10–14].]. The The mechanisms mechanisms of acquired of acquired resistance resistance to first-generation to first-generation EGFR-TKIsEGFR-TKIs are summarized are summarized in Figure in1 Figure. 1. Figure 1.FigureMechanisms 1. Mechanisms of acquired of acquired resistance resistance to first-generation to first-gene tyrosineration tyrosine kinase inhibitorskinase inhibitors (gefitinib (gefitinib and erlotinib)and erlotinib) [15,16]. EGFR,[15,16]. epidermal EGFR, ep growthidermal factor growth receptor; factor HER2, receptor; human HER2, epidermal human growth epidermal factor growth receptorfactor 2; MET, receptor mesenchymal–epithelial 2; MET, mesenchymal–epithelial transition factor; transition EMT, epithelial–mesenchymal factor; EMT, epithelial–mesenchymal transition; SCLC, small-celltransition; lung SCLC, cancer. small-cell lung cancer. T790M was the first reported acquired resistance gene [4]. The T790M mutation structurally T790M was the first reported acquired resistance gene [4]. The T790M mutation structurally inhibits the binding of first-generation EGFR-TKIs to the ATP binding site. When the T790M mutation inhibits the binding of first-generation EGFR-TKIs to the ATP binding site. When the T790M is added to the activation mutation of EGFR, the affinity of EGFR for ATP is increased, whereas the mutation is added to the activation mutation of EGFR, the affinity of EGFR for ATP is increased, binding property of EGFR-TKIs is relatively decreased. Hence, the downstream signal is not inhibited whereas the binding property of EGFR-TKIs is relatively decreased. Hence, the downstream signal is and the cancer is tolerated. It has been thought that a small number of cancer cells having a secondary not inhibited and the cancer is tolerated. It has been thought that a small number of cancer cells T790M mutation in addition to the active EGFR mutation may already be present prior to treatment having a secondary T790M mutation in addition to the active EGFR mutation may already be with EGFR-TKIs and gradually become dominant during treatment with first-generation EGFR-TKIs present prior to treatment with EGFR-TKIs and gradually become dominant during treatment with (e.g., gefitinib and erlotinib). However, recent research revealed that T790M-positive cells also occur first-generation EGFR-TKIs (e.g., gefitinib and erlotinib). However, recent research revealed that from initially T790M-negative single cells via genetic evolution [17]. T790M-positive cells also occur from initially T790M-negative single cells via genetic evolution [17]. Irreversible EGFR-TKIs were developed to overcome the T790M-mediated resistance. Irreversible EGFR-TKIs were developed to overcome the T790M-mediated resistance. These These second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) irreversibly bind to the cysteine second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) irreversibly bind to the cysteine residue of the EGFR [18]. Although the second-generation EGFR-TKIs exert an effect on T790M, residue of the EGFR [18]. Although the second-generation EGFR-TKIs exert an effect on T790M, the the half-maximal inhibitory concentration (IC50) is 30 to 100-fold higher than that observed with half-maximal inhibitory concentration (IC50) is 30 to 100-fold higher than that observed with the EGFR the activatedactivated mutation mutation of of EGFR[19 ].[19]. Integrated Integrated analysis analysis of two of two phase phase III studies III studies (LUX-Lung (LUX-Lung 3 and 3 and 6 6 trials)trials) showed showed thatafatinib that afatinib significantly significantly prolonged prolon overallged overall survival survival compared compared with chemotherapy with chemotherapy EGFR in patientsin patients with an with activated an activatedmutation EGFR mutation (hazard ratio,(hazard HR ratio, 0.81; 95%HR confidence0.81; 95% confidence interval, CI interval, 0.66 CI to 0.99; p = 0.037; 27.3 vs. 24.3 months, respectively) [20,21]. Furthermore, a randomized phase IIb Cells 2018, 7, 212 3 of 16 Cells 2018, 7, x FOR PEER REVIEW 3 of 17 trial comparing afatinib and gefitinib in patients with NSCLC harboring an active EGFR mutation 0.66 to 0.99; p = 0.037; 27.3 vs. 24.3 months, respectively)
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