Emerging Uses Of Biomarkers In Lung Cancer Management .

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Review ArticlePage 1 of 15Emerging uses of biomarkers in lung cancer management:molecular mechanisms of resistanceShirin Attarian1, Numa Rahman2, Balazs Halmos11Department of Oncology, 2Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USAContributions: (I) Conception and design: B Halmos; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV)Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Finalapproval of manuscript: All authors.Correspondence to: Balazs Halmos, MD. Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY10461, USA. Email: bahalmos@montefiore.org.Abstract: Management of patients with advanced non-small cell lung cancer (NSCLC) has recentlybeen transformed by molecularly targeted and immunotherapeutic agents. In patients with EGFR/ALK/ROS mutated NSCLC, first line molecular therapy is the standard of care. Moreover, immune checkpointinhibitors are revolutionary treatment options for advanced NSCLC and are now the standard of care infront-line or later line settings. Both classes of agents have led to improved patient outcomes, however,primary resistance and development of acquired resistance to both targeted and immunotherapeutic agentsis commonly observed, limiting the use of these agents in clinical settings. In this review, we will discussthe most recent advances in understanding the mechanisms of primary and acquired resistance, progressin the spectrum of assays detecting causative molecular events and the development of new generations ofinhibitors to overcome acquired resistance.Keywords: Resistance; molecular mechanisms; targeted therapy; epidermal growth factor receptor (EGFR);T790M; ALK; MET; ROS; immune checkpoint inhibitorSubmitted May 24, 2017. Accepted for publication Jun 28, 2017.doi: 10.21037/atm.2017.07.18View this article at: ionResearch over the last decade has transformed themanagement of patients with advanced non-small celllung cancer (NSCLC) with the recognition of molecularlydefined subsets of tumors with unique sensitivities totargeted therapeutics, such as patients with EGFR/ALK/ROS-mutated lung adenocarcinoma. Upfront moleculartherapy is now the standard of care for optimization oftreatment, and patient outcomes have greatly improved.In addition, an expanding group of other molecularalterations are continuing to be recognized and biomarkerdriven immunotherapeutic strategies have yielded dramaticadvances in patient management. However, acquiredresistance to both targeted and immunotherapeutic agentshave become a pivotal issue limiting the long-term benefitof such therapies. In the current review, we will highlight Annals of Translational Medicine. All rights reserved.the most significant advances in our understanding ofmechanisms of primary and acquired drug resistance,strategies to detect secondary molecular events, anddrug development strategies yielding new generations ofinhibitors with increasing success to overcome acquiredresistance (Figure 1).Epidermal growth factor receptor (EGFR)The EGFR gene, located on chromosome 7p12-13, encodesfor a HER family receptor tyrosine kinase (RTK) that uponactivation, will “switch on” several downstream signalingpathways important in cell survival and proliferation (1).Activating mutations in the tyrosine kinase domain of theEGFR gene are seen in 10–15% of non-squamous NSCLCand are responsible for tumor growth, proliferation,atm.amegroups.comAnn Transl Med 2017;5(18):377

Attarian et al. Mechanisms of resistancePage 2 of 15Extracellular compartmentBypass Signaling pathways(MET, HER )T cellMutatedEGFRPD1P-gp ibC797SPRASRAFMEK1/2PI3KAKTmTORSCLC chemotherapyERK/MAPKEMT/phenotypic changeCell proliferation, invasion, migration, inhibition of apoptosisFigure 1 General mechanisms of resistance.invasion and metastases by promoting pro-proliferativeand anti-apoptotic effects. These mutations occur morecommonly in tumors in women, non-smokers and patientsof Asian ethnicity and can be as frequent as 50–60% in lungadenocarcinomas in Asian women (2,3).Two so-called “classic” mutations account for 90%of the known activating EGFR mutations: L858R pointmutation on exon 21 and in-frame deletions around theconserved LREA motif of exon 19 (2,3). The presence ofsuch activating EGFR mutations serves as a biomarker aswell as a target for therapy with EGFR-tyrosine kinaseinhibitors (TKI). Several clinical studies revealed thatresponse rates (RRs) to first generation EGFR-TKIs, suchas gefitinib and erlotinib, in patients harboring an EGFRactivating mutation are 50–80% and can lead to durable Annals of Translational Medicine. All rights reserved.responses with progression free survival in the 8–12 monthsrange (4-8). In 2012, a meta-analysis of six randomizedcontrolled trials confirmed significant improvement inoverall response rate (ORR) and doubling of progressionfree survival (PFS) in patients with advanced EGFRmutated NSCLC receiving first-line EGFR-TKI, ascompared to conventional chemotherapy (9). Therefore,EGFR-TKIs are the current standard treatment for thesepatients and frontline molecular testing is now part ofroutine management (4,9).However, resistance to EGFR-TKIs poses a majorclinical problem, and can be categorized as primary oracquired. Primary resistance refers to de novo lack ofresponse to the targeted therapy, while acquired resistanceis defined as progression of disease after an initial period ofatm.amegroups.comAnn Transl Med 2017;5(18):377

Annals of Translational Medicine, Vol 5, No 18 September 2017clinical response (10,11).Page 3 of 15not be actionable, this may be important in order to riskstratify patients.Primary resistanceSeveral mechanisms of primary resistance to EGFR-TKIshave been described.First generation EGFR-TKIs are not effective in patientswith the gatekeeper EGFR T790M mutation which can bepresent as a germline mutation in rare familial clusters. Thismutation will be discussed in detail later in this review (10).Another example of primary resistance to EGFR TKIs isthe EGF exon 20 insertion mutation. The RR of NSCLCswith EGFR exon 20 insertion mutation to EGFR-TKIs isbelow 5% (12). The mechanism for this primary resistancehas been described by Yasuda et al. (12), 80–90% ofactivating EGFR exon 20 mutations cause insertion of oneto four amino-acids beyond the C-helix of the tyrosinekinase domain, forming a wedge at the end of the C helixthat promotes the active kinase and leaves the adenosinetriphosphate binding pocket unaltered. Interestingly, anEGFR exon 20 insertion mutation sensitive to the EGFRTKIs was also identified (EGFR A763 Y764insFQEA).Structurally, this mutation is very different from other exon20 insertions and more closely resembles the L858R andexon 19 deletion mutations. At present, the standard ofcare for TKI-resistant exon 20 mutated EGFR tumors isconventional chemotherapy (13,14). Efforts are being madeto develop EGFR targeting agents with activity against thisimportant class of mutation (e.g., AP32788 NCT02716116).Another mechanism of primary resistance is conferredby polymorphisms in the Bim gene. Bim is a potent proapoptotic protein and its expression is suppressed in EGFRmutated lung cancers. TKI therapy can upregulate Bimexpression and allow for cell death and tumor regression. Inthe case of certain inherited Bim gene polymorphisms, thepro-apoptotic domain is not present and TKI therapy is lesssuccessful with shorter duration of response than in othergenotypes (15).Finally, as expected, EGFR-TKI therapy is not effectiveagainst tumors with concurrent activating mutations in genesdownstream of EGFR such as K-ras and BRAF or againsttumors harboring other oncogenic gene alterations (10).Canale et al. (16) observed that TP53 tumor suppressorgene mutations, especially exon 8 mutations, reduce theRR to TKIs. Inferior outcomes in the presence of p53mutations had been similarly noted by the Lung CancerMutation Consortium (17). TP53 mutations occur in about30%–40% of NSCLCs and while TP53 mutations might Annals of Translational Medicine. All rights reserved.Acquired resistanceAcquired resistance to EGFR-TKIs typically developswithin 6–18 months of starting therapy (11). Biopsy andsequencing of tumors in patients with disease progressionon an EGFR TKI as well as in vitro and mouse studies haveled to the discovery of potential mechanisms of acquiredresistance as well as novel and effective ways of overcomingcertain resistance mechanisms (18).T790M mutationThe most common mechanism of acquired resistance,accounting for up to 60% of cases, is a secondary mutationof EGFR gene, leading to the substitution of methioninefor threonine at position 790 (T790M) (10). Methionine’slarge side chain causes steric hindrance and reduces theability of 1st generation EGFR-TKIs such as erlotinib andgefitinib to bind to the ATP-kinase pocket. In addition,this mutation changes the dynamics at the binding site suchthat ATP, rather than the ATP-competitive EGFR-TKIs isthe favored substrate. This leads to a 1,000-fold increasedresistance against the EGFR-TKIs (10,18).Several studies have been done to determine if tumorcells containing the T790M mutation are present prior toEGFR-TKI treatment initiation or if they develop fromcancer stem cells during treatment. These studies havefound very few TKI-resistant cells prior to treatmentthereby suggesting that the T790M mutation morecommonly arises due to selective pressure during EGFRTKI therapy (10,19). Three other point mutations havebeen implicated in EGFR-TKI resistance (D761Y, L747S,T854A), however they have been reported only occasionallyand their mechanism of resistance is less understood (10).Activation of bypass signaling pathwaysA second mechanism of acquired resistance is throughthe activation of bypass signaling pathways. For example,amplification of the MET gene has been seen in 5–22%of NSCLC patients who develop acquired resistance toEGFR-TKIs. These amplifications are seen in very lowrates in tumors that have not yet undergone treatmentwith an EGFR-TKI. Thus, it has been postulated thatunder the selective pressure of EGFR-TKI therapy, cellsatm.amegroups.comAnn Transl Med 2017;5(18):377

Attarian et al. Mechanisms of resistancePage 4 of 15with dual EGFR and MET activation can undergo clonalselection. Ultimately, these EGFR MET mutated cellsform the bulk of the tumor leading to clinical resistanceagainst EGFR-TKIs. In vitro, MET amplification has beenreported in gefitinib-resistant cell lines and dual EGFR andMET inhibition has been successful in inducing apoptosisin this case (20,21).MET activation by its ligand HGF may also be anothermechanism contributing to acquired resistance. In a fewstudies, it has been noted that HGF is expressed in highlevels in 29% of patients with primary resistance and 61%of patients with acquired resistance (22). If future studiesvalidate this mechanism in vivo, targeted therapy againstHGF can be a potential strategy to treat this subset ofpatients (10).HER2 amplification is another alternative signalingpathway that plays a role in acquired resistance to EGFRTKIs and has been noted in up to 13% of patients (10).In a phase Ib study of patients with NSCLC resistant toerlotinib/gefitinib, dual inhibition of EGFR and HER2 withafatinib and cetuximab demonstrated promising activityleading to median PFS of 4.7 months (23). Another bypasssignaling mechanism that has been recently implicatedin afatinib-resistant PC9 cells is the IGF1R pathway—increased expression of insulin-like growth factor bindingprotein 3 (IGFBP-3) enhances IGF1R activity leading toincreased AKT phosphorylation and subsequent cell cycleprogression (24).Phenotypic changesYet another mechanism of acquired resistance is throughphenotypic alterations. Epithelial mesenchymal transition(EMT) is defined as the loss of epithelial markers and asubsequent gain of mesenchymal features (10). NSCLCcells that undergo EMT lose sensitivity to EGFR-TKIs (25).Furthermore, when the epithelial phenotype is restoredin these EGFR-mutated NSCLC cell lines, they becomesensitive again to EGFR-TKIs (26). The transition betweenepithelial and mesenchymal phenotypes is likely influencedby the AXL RTK. A high level of expression of AXL RTKhas been implicated in acquired resistance to erlotinib,and over-expression of this same RTK has been noted inNSCLC cells with the mesenchymal subtype (10,27). Takentogether, it seems as though AXL plays a significant role inthe acquired resistance to EGFR-TKIs and may one day bean effective pharmaceutical target. In fact, a recent reportof tumor genomic profiling cites the case of a patient with Annals of Translational Medicine. All rights reserved.lung adenocarcinoma and pleural carcinomatosis whosegenome analysis showed focal gain of chromosome 19q1213.11, including AXL. He was enrolled in a Phase I trialof MGCD265, a TKI targeting MET and AXL with adramatic response and near resolution of lung infiltrates onimaging in just 2 months (28).A different kind of phenotypic alteration happens whenthe NSCLC cells undergo histological transformation tosmall cell lung cancer (SCLC). This has been reported in3–14% of patients with acquired resistance to EGFR-TKIwho underwent re-biopsy. In a recent study Lee et al. (29)investigated 21 patients with advanced EGFR-mutatedNSCLC that transformed into SCLC. Whole genomesequencing was performed at different time points duringdisease evolution. It was concluded that TKI-resistantEGFR-mutated NSCLC and SCLCs share a common clonalorigin and the clonal divergence occurs before the EGFRTKI therapy. Complete inactivation of RB1 and TP53 wereobserved from the early NSCLC stages in these tumors.There have been multiple cases that reported good responseto SCLC chemotherapy regimens once the NSCLCundergoes this histological transformation underlining theimportance of testing for such alterations (10,30).Pharmacodynamic limitationsAnother limitation to the use of first and second generationTKIs is the inability of these drugs to fully penetrate theblood brain barrier (BBB) and enter the central nervoussystem (CNS). Patients can often develop CNS metastasesduring treatment, even when their extracranial tumors arestill under control (31). CNS concentrations of all currentlyavailable agents are lower than plasma [gefitinib has a CSFconcentration approximately 1% of serum and erlotinibhas a CSF concentration 5% of serum (32,33)]. ManyEGFR TKIs that have been designed for improved CNSpenetration are currently under investigation. One suchdrug, AZD3759 has shown promise with CNS penetrationadequate enough to promote tumor shrinkage in patientswith brain and leptomeningeal metastases in addition to atolerable side-effect profile (34).Treatment approaches to overcome resistanceThird generation EGFR TKIsKnowledge of the biological mechanisms behind acquiredresistance to EGFR-TKIs has led to the development of 3rdatm.amegroups.comAnn Transl Med 2017;5(18):377

Annals of Translational Medicine, Vol 5, No 18 September 2017generation TKIs that specifically target the EGFR T790Mmutant cells. The side-effect profile of these new TKIs ismore favorable given that they spare WT EGFR (10,11).Of the 3rd generation TKIs, osimertinib has progressedthe furthest in clinical development. Osimertinib, an oralirreversible agent with CNS penetration, had initially beenapproved by the FDA under the Breakthrough TherapyDesignation Program based on outstanding results from theAURA-1 and AURA-2 studies suggestive of great efficacywith RRs in the 50–60% range in EGFR T790M-mutatedcases as well as favorable toxicity profiles. Recently, Moket al. published the results of a confirmatory, randomized,open-label, international, phase 3 (AURA 3) trial to showthe superiority of osimertinib over platinum plus pemetrexedchemotherapy in patients with confirmed T790M-positiveadvanced NSCLC after first-line EGFR-TKI therapy.Median PFS was significantly longer with osimertinibas compared to chemotherapy (10.1 vs. 4.4 months)and objective RR was significantly better with osimertinib(71% vs. 31%). Even among the 144 patients in the trialwho had CNS disease, osimertinib performed better,PFS was 8.5 months with osimertinib vs. 4.2 months withchemotherapy. Adverse events of grade 3 or higher weremore common in the chemotherapy group as compared toosimertinib (47% vs. 23%) (35). These results led to fullFDA approval of osimertinib in 2017.Unfortunately, tumor samples from patients treated withosimertinib have already revealed that emerging resistancewill remain a key shortcoming of this class of drugs. TheEGFR C797S mutation appears to be the most dominantresistance mechanism, with frequency as high as 20–40% (36).This mutation is very logical from a biochemical perspectiveas osimertinib and other irreversible EGFR inhibitorscovalently bind to C797 of EGFR gene and this mutationinterferes with such binding, thus drastically diminishingactivity. Interestingly, the allelic context of C797S seemsto have treatment implications—when the T790M andC797S mutations occur in trans (on separate alleles), acombination of first and third generation TKIs can restoreEGFR inhibition. But, if the mutations are in cis (on sameallele), the cells will not be sensitive to any available EGFRTKI (37). Understanding of such novel resistancemechanisms is already leading to innovative approaches ofpreventing/overcoming such resistance.For example, a new compound called EAI045, whichacts as an allosteric inhibitor of the TK domain of EGFR,could be a promising agent in overcoming resistance to 3rdgeneration TKIs. In mouse models, EAI045 in combination Annals of Translational Medicine. All rights reserved.Page 5 of 15with cetuximab, an antibody that stops EGFR dimerization,has been shown to be effective against the L8585R/T790Mand L858R/T790M/C797S EGFR mutants (38). Anotherdrug regimen that is a powerful candidate to overcometriple-mutant EGFR is the combination of cetuximab withbrigatinib, a potent and selective ALK/EGFR T790Minhibitor. This regimen showed excellent efficacy in del19/T790M and del19/T790M/C797S cell lines as well as indel19/T790M/C797S xenograft mouse models (39).MET inhibition for bypass signalingDual inhibition of EGFR and MET has been studied intwo Phase III trials: the MET-Lung trial that investigatedthe combination of erlotinib onartuzumab, a monoclonalantibody against MET, as well as the MARQUEE trial thatcompared erlotinib tivantinib, a MET TKI. However,neither of these studies met their primary endpoint ofimproving OS, maybe due to the fact that the studies didnot focus on the EGFR-mutated population (10,40).Since successful treatment with erlotinib and crizotinib(a potent MET and ALK inhibitor) has been described incase reports (41,42), a phase I trial was designed to studythis combination. However, in the 26 patients in the trial,the MTD for the two drugs was lower than the approveddose of the individual drugs, so phase II trials have not beeninitiated yet (43). Further trials have also been halted for thecombination regimen of erlotinib the anti-MET antibodyLY2875358 because of initial disappointing results (10).There are more promising biomarker-driven studiesthat are currently being pursued. Preliminary studies ofanother MET inhibitor, capmatinib revealed that patientswith cMET gene copy number 5 had an ORR of 40% (44).At present, a three-arm study has been designed to studycapmatinib by itself and in combination with erlotinib ascompared to standard chemotherapy in EGFR-mutatedNSCLC patients specifically with c-MET copy number 6(NCT02468661).Another study will compare the combination of gefitiniband a MET inhibitor named tepotinib versus chemotherapyas sec

Emerging uses of biomarkers in lung cancer management: molecular mechanisms of resistance Shirin Attarian1, Numa Rahman2, Balazs Halmos1 1Department of Oncology, 2Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

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