Antitumor activity of osimertinib in NSCLC harboring EGFR exon 20 insertions.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9030-9030 ◽  
Author(s):  
Jonathan Riess ◽  
Nicolas Floch ◽  
Matthew Martin ◽  
Jonathon Orme ◽  
Anna Staniszewska ◽  
...  
Keyword(s):  
Unmet Need ◽  
Tumor Growth Inhibition ◽  
Drug Discontinuation ◽  
Tumor Shrinkage ◽  
In Vivo Experiments ◽  
Activating Mutation ◽  
Exon 20 ◽  
Egfr Tki ◽  
Egfr Tkis

9030 Background: EGFR exon 20 insertions (Ex20Ins), the 3rd most common EGFR activating mutation, are generally unresponsive to 1st and 2nd generation EGFR-TKIs. Development of EGFR-TKIs that effectively target NSCLC with Ex20Ins mutations represents a major unmet need. Osimertinib is an EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M, but the potential of osimertinib remains to be fully assessed in patients (pts) with Ex20Ins NSCLC. Methods: CRISPR engineered Ex20Ins cell line xenografts representing the two most common Ex20Ins (D770_N771InsSVD and V769_D770InsASV) and pt derived xenograft (PDX) of 3 EGFR Ex20Ins (V769_D770InsASV, M766_A767insASV, H773_V774insNPH) were used for in vivo experiments. Xenografts were treated by oral gavage with vehicle, erlotinib (50 mg/kg/day) or afatinib (20 mg/kg/day), osimertinib metabolite AZ5104 (50 mg/kg/day) and osimertinib (25 mg/kg/day) and assessed for tumor growth inhibition (TGI). Immunoblotting was performed for EGFR and relevant signaling pathways. A pt from whom the V769_D770InsASV Ex20ins PDX was derived was treated on a UC Davis IRB approved protocol with osimertinib at 160 mg PO once-daily (QD). Results: At completion of treatment, QD administration of osimertinib or AZ5104 induced significant TGI in xenografts across the 4 EGFR Ex20ins tested (range 60-95% TGI, p < 0.001 compared to control for all models) that was superior to either afatinib or erlotinib. Robust decrease in p-EGFR, p-ERK, p-Akt, p-Stat3 was observed with osimertinib treatment. The patient corresponding to the V769_D770InsASV Ex20ins PDX treated with osimertinib exhibited clinical improvement and tumor shrinkage; unfortunately he was found to have interstitial pneumonitis that necessitated drug discontinuation. Conclusions: Osimertinib at clinically representative doses has in vivo activity across multiple EGFR Ex20ins that comprising the most common Ex20ins detected in patients (~50% prevalence); metabolite AZ5104 may contribute to efficacy. Tumor shrinkage was observed in a patient with lung cancer harboring an Ex20ins treated for a limited time with osimertinib. Based on this in vivo xenograft and pt data, osimertinib warrants further study in pts with EGFR Ex20ins NSCLC.

scholarly journals MiR-125b-5p Inhibited The Progression of Hepatoblastoma As A Shared miRNA of The lncRNA NEAT1 and YES1

2020 ◽  
Author(s):  
Zhu Jin ◽  
Yutong Chen ◽  
Yuchen Mao ◽  
Mingjuan Gao ◽  
Zebing Zheng ◽  
...  
Keyword(s):  
Clinicopathological Characteristics ◽  
Luciferase Reporter ◽  
Tumor Growth Inhibition ◽  
Invasion And Migration ◽  
In Vivo Experiments ◽  
Reporter Assays ◽  
And Migration ◽  
Relationship Of

Abstract Background: microRNAs have been studied widely in hepatoblastoma. However, the role of miR-125b-5p and its relationship with the lncRNA sNEAT1 and YES1 in hepatoblastoma have not been reported previously. We aimed to reveal the role of NEAT1/miR-125b-5p/YES1 in the progression of hepatoblastoma.Methods: We collected tumor tissues and their adjacent tissues from 12 hepatoblastoma patients. qRT-PCR was applied to detect the expression of miR-125b-5p, and the relationship of miR-125b-5p with clinicopathological characteristics was analyzed. Dual luciferase reporter assays and RNA pull down assays were used to identify the relationships among NEAT1, miR-125b-5p and YES1. CCK8, Transwell assays and wound healing assays were used to examine cell viability, invasion and migration. In vivo experiments were also applied to detect the effect of miR-125b-5p on hepatoblastoma.Results: miR-125b-5p was significantly downregulated in hepatoblastoma tissue and cells. The higher the PRETEXT grade, the lower the miR-125b-5p level. NEAT1 could bind to miR-125b-5p and inhibit its expression. miR-125b-5p could target YES1 and inhibit its expression. Overexpression of miR-125b-5p decreased the proliferation, invasion, and migratory ability of hepatoblastoma cells. YES1 could rescue the above effects. At the same time, overexpression of miR-125b-5p resulted in decreased YES1 and tumor growth inhibition in vivo.Conclusion: miR-125b-5p acted as a shared miRNA of NEAT1 and YES1 in hepatoblastoma. Overexpression of miR-125b-5p could target YES1 and inhibit its expression, therefore inhibiting the progression of hepatoblastoma.

scholarly journals DARPP-32 promotes ERBB3-mediated resistance to molecular targeted therapy in EGFR-mutated lung adenocarcinoma

2021 ◽  
Author(s):  
Sk. Kayum Alam ◽  
Yongchang Zhang ◽  
Li Wang ◽  
Zhu Zhu ◽  
Christina E. Hernandez ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Disease Progression ◽  
Cancer Progression ◽  
Lung Tumor ◽  
Genetic Alterations ◽  
In Vivo Studies ◽  
Driver Mutations ◽  
Egfr Tki ◽  
Egfr Tkis

AbstractWhile molecular targeted therapies have improved prognoses of advanced stage lung adenocarcinoma expressing oncogenic driver mutations, acquired therapeutic resistance continues to be a major problem. Epidermal growth factor receptor (EGFR) activating mutations are among the most common targetable genetic alterations in lung adenocarcinoma, and EGFR tyrosine kinase inhibitors (TKIs) are recommended first-line therapy for EGFR mutation positive cancer patients. Unfortunately, most patients develop resistance to EGFR TKIs and rapid disease progression occurs. A better mechanistic understanding of therapy refractory cancer progression is necessary to develop new therapeutic approaches to predict and prevent acquired resistance to EGFR TKIs. Here, we identify a new mechanism of ERBB3-mediated resistance to EGFR TKIs in human lung adenocarcinoma. Specifically, we show that dopamine and cyclic AMP-regulated phosphoprotein, Mr 32000 (DARPP-32) physically recruits ERBB3 to EGFR to mediate a switch from EGFR homodimers to EGFR:ERBB3 heterodimers to bypass EGFR TKI-mediated inhibition to potentiate ERBB3-dependent activation of oncogenic AKT and ERK signaling that drives therapy refractory tumor cell survival. In a cohort of paired tumor specimens derived from 30 lung adenocarcinoma patients before and after the development of EGFR TKI refractory disease progression, we reveal that DARPP-32 as well as kinase-activated EGFR and ERBB3 proteins are overexpressed upon acquired EGFR TKI resistance. In vivo studies suggest that ablation of DARPP-32 protein activity sensitizes gefitinib-resistant lung tumor xenografts to EGFR TKI treatment, while DARPP-32 overexpression increases gefitinib-refractory lung cancer progression in gefitinib-sensitive lung tumors orthotopically xenografted into mice. Taken together, our findings introduce a DARPP-32-mediated, ERBB3-dependent mechanism used by lung tumor cells to evade EGFR TKI-induced cell death, potentially paving the way for the development of new therapies to prevent or overcome therapy-refractory lung adenocarcinoma progression.

scholarly journals Sutureless repair of corneal injuries using naturally derived bioadhesive hydrogels

2019 ◽  
Vol 5 (3) ◽  
pp. eaav1281 ◽  
Author(s):  
Ehsan Shirzaei Sani ◽  
Ahmad Kheirkhah ◽  
Devyesh Rana ◽  
Zhongmou Sun ◽  
William Foulsham ◽  
...  
Keyword(s):  
Low Cost ◽  
Unmet Need ◽  
Defect Model ◽  
Sutureless Repair ◽  
In Vivo Experiments ◽  
High Adhesion ◽  
Common Causes ◽  
Corneal Regeneration

Corneal injuries are common causes of visual impairment worldwide. Accordingly, there is an unmet need for transparent biomaterials that have high adhesion, cohesion, and regenerative properties. Herein, we engineer a highly biocompatible and transparent bioadhesive for corneal reconstruction using a visible light cross-linkable, naturally derived polymer, GelCORE (gel for corneal regeneration). The physical properties of GelCORE could be finely tuned by changing prepolymer concentration and photocrosslinking time. GelCORE revealed higher tissue adhesion compared to commercial adhesives. Furthermore, in situ photopolymerization of GelCORE facilitated easy delivery to the cornea, allowing for bioadhesive curing precisely according to the required geometry of the defect. In vivo experiments, using a rabbit stromal defect model, showed that bioadhesive could effectively seal corneal defects and induce stromal regeneration and re-epithelialization. Overall, GelCORE has many advantages including low cost and ease of production and use. This makes GelCORE a promising bioadhesive for corneal repair.

scholarly journals PKCδ-mediated SGLT1 upregulation confers the acquired resistance of NSCLC to EGFR TKIs

Oncogene ◽  
2021 ◽  
Author(s):  
Chia-Hung Chen ◽  
Bo-Wei Wang ◽  
Yu-Chun Hsiao ◽  
Chun-Yi Wu ◽  
Fang-Ju Cheng ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Tki Treatment ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis

AbstractThe tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have been widely used for non-small cell lung cancer (NSCLC) patients, but the development of acquired resistance remains a therapeutic hurdle. The reduction of glucose uptake has been implicated in the anti-tumor activity of EGFR TKIs. In this study, the upregulation of the active sodium/glucose co-transporter 1 (SGLT1) was found to confer the development of acquired EGFR TKI resistance and was correlated with the poorer clinical outcome of the NSCLC patients who received EGFR TKI treatment. Blockade of SGLT1 overcame this resistance in vitro and in vivo by reducing glucose uptake in NSCLC cells. Mechanistically, SGLT1 protein was stabilized through the interaction with PKCδ-phosphorylated (Thr678) EGFR in the TKI-resistant cells. Our findings revealed that PKCδ/EGFR axis-dependent SGLT1 upregulation was a critical mechanism underlying the acquired resistance to EGFR TKIs. We suggest co-targeting PKCδ/SGLT1 as a potential strategy to improve the therapeutic efficacy of EGFR TKIs in NSCLC patients.

scholarly journals Polyvinyl Alcohol Carbazate as a Polymer-Based Antitumoral Agent

2021 ◽  
Vol 10 ◽  
Author(s):  
Felix Sellberg ◽  
Robin Fröbom ◽  
Christian Binder ◽  
Erik Berglund ◽  
David Berglund
Keyword(s):  
Mouse Model ◽  
Polyvinyl Alcohol ◽  
Growth Inhibition ◽  
Unmet Need ◽  
Biological Properties ◽  
Tumor Growth Inhibition ◽  
Athymic Mice ◽  
Ki 67

Development of treatment resistance is a major concern during treatment of cancer, and there is an unmet need for therapeutic strategies with novel modes of action. Polyvinyl alcohol carbazate (PVAC) is a polymer compound with unique biological properties. Herein, we describe the antitumoral effects of PVAC. Three well-established cell lines GIST-T1, B16.F10, and A375 were used to determine the in vitro antitumoral effects of PVAC. Assessments included light microscopy, cell viability, cell cycle, and apoptosis assays. In vivo treatment safety and efficacy were characterized in one immunocompetent (B16.F10) mouse model and one athymic nude (MDA-MB-231) mouse model. Excised tumors were measured, weighed, stained for Ki-67, CD3, and histopathologically evaluated. Intact PVAC expressed a non-linear dose-response antitumoral effect in vitro, whereas its separate components, PVA and carbazate, did not display antitumoral effects alone. In vivo, PVAC induced a significant intratumoral CD3+ T-cell recruitment in immunocompetent mice (B16.F10), which was associated with tumor growth inhibition. Although growth inhibition was not significant in athymic mice (MDA-MB-231), histopathological evaluation detected an increase in stromal tissue and leukocyte infiltration. In conclusion, we present evidence for PVAC antitumoral effects both in vitro and in vivo. The mode of action was not elucidated in vitro, but a potential mechanism of in vivo activity was observed, characterized by an increase of immune cells into both immunocompetent and athymic mice. This finding warrants further study to validate its possible role as an immunomodulatory polymeric agent.

Clinical efficacy of icotinib in patients with advanced non-small cell lung cancer harboring EGFR exon 18, 20 and 21 uncommon mutations.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14050-e14050
Author(s):  
Chunwei Xu ◽  
Wen-xian Wang ◽  
Meiyu Fang ◽  
Wu Zhuang ◽  
Gen Lin ◽  
...  
Keyword(s):  
Clinical Efficacy ◽  
Gene Mutations ◽  
Egfr Mutations ◽  
Double Blind ◽  
Patient Response ◽  
Previously Treated ◽  
Exon 20 ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis

e14050 Background: EGFR gene mutations were discovered in some of NSCLC patients. Two major EGFR mutations include 19del and L858R. These mutations account for more than 90% of all mutations related to EGFR TKIs sensitivity. Icotinib, an EGFR TKI, showed equivalent response rates and better tolerability compared with gefitinib, double blind trial (ICOGEN) with advanced NSCLC previously treated in China. In addition, other uncommon mutations have been identified. The efficacy of icotinib in patients harboring these mutations to icotinib is still unknown. This study investigated the efficacy of icotinib in patients carrying G719X/E709X/G724S in exon 18, S768I/20 insertions/T790M/V769M in exon 20 and L861Q/L833F in exon 21. Methods: Retrospectively analysed 24 cases of 18 exon, 58 cases of 20exon and 17 cases of 21 exon uncommon mutation NSCLC patients until the progress of the disease or the emergence of the side effects and clinical efficacy was observed after months followed-up. Results: 99 patients with G719X/E709X/G724S/S768I/20 insertions/T790M/V769M/ L861Q/L833F mutations were enrolled. The patient response rate and disease control rate were 31.58%, 66.66%, 0, 25.00%, 11.11%, 4.76%, 0%, 23.53%, 0% and 73.68%, 66.66%, 100%, 80.00%, 44.44%, 47.62%, 100%, 64.71%, 100%, respectively. The mPFS were 2.7 months, respectively. Patients with L833F mutation manifested the longest mPFS(4.2 months), followed by those with G724S mutation(3.5 months), S768I and V769M(3.2 months), E709X(3.1 months), G719X(2.8 months), L861Q(2.2 months), exon 20 insertions(1.9 months) and T790M(1.6 months). Patients with complex mutations show a better PFS than those with single mutations(G719X mutations 3.3 months vs 2.6 months, P = 0.029; E709X 7.2 months vs 2.7 months, P = 0.225; S768I mutations 2.2 months vs 3.3months, P = 0.174; T790M 2.45 months vs 2.9 months, P = 0.845; L861Q mutations 2.1 months vs 5.6 months, P = 0.065 ).Conclusions: Icotinib is less effective in patients with uncommon mutations than in those with common mutations. Patients with complex mutations benefited more from icotinib than those with single mutations.

Real-world treatment outcome of advanced Chinese NSCLC EGFR exon 20 insertion patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9043-9043
Author(s):  
Yan Wang ◽  
Guangjian Yang ◽  
Jun Li ◽  
Haiyan Xu ◽  
Lu Yang ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Real World ◽  
Platinum Based Chemotherapy ◽  
Never Smokers ◽  
Tki Treatment ◽  
Exon 20 ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis ◽  
Line Chemotherapy

9043 Background: Treatment outcome of advanced EGFR exon20 insertion (ex20ins) patients with 1st- or 2nd-line chemotherapy and EGFR TKIs remains limited. Methods: Retrospective real-world analysis of clinical, molecular, and treatment outcome of a web-based patient registry and hospital chart review. Results: Between 9/13/18-10/22/18, 165 EGFR ex20ins NSCLC patients treated in 99 hospitals from 26 different regions in China were registered. Data cutoff was 12/20/18. EGFR ex20ins were determined by commercial NGS (84%) or PCR (16%). 41 different molecular subtypes of EGFR ex20ins were identified. Ala767_Val769dupASV was the most common (23.0%) followed by Ser768_Asp770dupSVD (17.6%). 61% were females, 77% never-smokers, and CNS mets occurred in 22.4% of patients at time of diagnosis. Median PFS was significantly longer in patients who received 1st-line platinum-based chemotherapy (N = 105) (6.4m; 95% CI:5.7-7.1) vs. EGFR TKI (all generations, N = 23) (2.9m; 95%CI:1.5-4.3; P < 0.001) or vs. EGFR TKI (1G, N = 14) (2.6m; 95%CI:0.8-4.4; P < 0.001). Median PFS was numerically longer in patients who received 2nd-line paclitaxel-based chemotherapy (N = 34) (4.1m; 95%CI:3.3-4.9) versus patients who received 2nd-line EGFR TKIs (N = 18) (2.0m; 95%CI:0.8-3.2; P = 0.342). Patients with CNS mets (N = 21) had shorter median PFS with 1st-line chemotherapy than those without CNS mets (N = 84) (5.5m; 95%CI:0.7-10.3 vs. 6.4m; 95%CI:5.8-7.0; P = 0.694). Patients with CNS mets had numerically shorter median PFS with 1st-line EGFR TKI (N = 7) than those without CNS mets (N = 16) (2.0m; 95%CI:0.8-3.2 vs. 2.9m; 95%CI:2.1-3.7; P = 0.077). Conclusions: Chemotherapy is superior to current approved EGFR TKIs as 1st- or 2nd-line treatment of EGFR ex20ins. Patients with CNS mets had numerically poorer PFS with chemotherapy and EGFR TKI treatment. Targeted therapy against EGFR ex20ins with CNS activity is needed.

scholarly journals NIR Light-Triggered Chemo-Phototherapy by ICG Functionalized MWNTs for Synergistic Tumor-Targeted Delivery

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2145
Author(s):  
Lu Tang ◽  
Aining Zhang ◽  
Yijun Mei ◽  
Qiaqia Xiao ◽  
Xiangting Xu ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Targeted Delivery ◽  
Near Infrared ◽  
Drug Carrier ◽  
Tumor Growth Inhibition ◽  
In Vivo Experiments ◽  
Promising Application ◽  
Targeting Ability

The combinational application of photothermal therapy (PTT), chemotherapy, and nanotechnology is a booming therapeutic strategy for cancer treatment. Multi-walled carbon nanotube (MWNT) is often utilized as drug carrier in biomedical fields with excellent photothermal properties, and indocyanine green (ICG) is a near-infrared (NIR) dye approved by FDA. In addition, ICG is also a photothermal agent that can strongly absorb light energy for tumor ablation. Herein, we explored a synergistic strategy by connecting MWNT and a kind of ICG derivate ICG-NH2 through hyaluronic acid (HA) that possesses CD44 receptor targeting ability, which largely enhanced the PTT effect of both MWNT and ICG-NH2. To realize the synergistic therapeutic effect of chemotherapy and phototherapy, doxorubicin (DOX) was attached on the wall of MWNT via π–π interaction to obtain the final MWNT-HA-ICG/DOX nanocomplexes. Both in vitro and in vivo experiments verified the great therapeutic efficacy of MWNT-HA-ICG/DOX nanocomplexes, which was characterized by improved photothermal performance, strengthened cytotoxicity, and elevated tumor growth inhibition based on MCF-7 tumor models. Therefore, this synergistic strategy we report here might offer a new idea with promising application prospect for cancer treatment.

Oncogene HSPH1 modulated by the rs2280059 genetic variant diminishes EGFR-TKIs efficiency in advanced lung adenocarcinoma

2020 ◽  
Vol 41 (9) ◽  
pp. 1195-1202
Author(s):  
Yankang Li ◽  
Nasha Zhang ◽  
Li Zhang ◽  
Yemei Song ◽  
Jie Liu ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Nucleotide Polymorphisms ◽  
Epidermal Growth ◽  
Tki Treatment ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy is effective for most advanced non-small-cell lung cancer (NSCLC) patients with mutant EGFR, some patients show little or no response. Germline variations, such as single-nucleotide polymorphisms (SNPs), have been proved to be involved in disease progression after EGFR-TKI therapy. In this study, we hypothesized that the functional HSPH1 SNP may affect gene expression and, thus, prognosis of NSCLC patients treated with EGFR-TKIs. We systematically examined impacts of HSPH1 SNPs on NSCLC survival in two independent cohorts consisted of 319 EGFR-TKI treated stage IIIB/IV NSCLC patients. The promoter rs2280059 polymorphism was significantly associated with patient survival in both cohorts. In vitro and In vivo assays elucidated that rs2280059 G allele shows higher capability to drive HSPH1 promoter activities. Silencing HSPH1 significantly increases the antineoplastic effects of gefitinib on NSCLC cells. Our findings demonstrated potential implications of HSPH1 in clinic, which may lead to better understanding and outcome assessment of EGFR-TKI treatment.

scholarly journals Preclinical characterization of mobocertinib highlights the putative therapeutic window of this novel EGFR inhibitor to EGFR exon 20 insertion mutations

2020 ◽  
Author(s):  
Pedro E. N. S. Vasconcelos ◽  
Ikei S. Kobayashi ◽  
Susumu S. Kobayashi ◽  
Daniel B. Costa
Keyword(s):  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Therapeutic Window ◽  
Mechanisms Of Resistance ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Exon 20 ◽  
Egfr Tki ◽  
Insertion Mutations ◽  
Egfr Tkis

AbstractBackgroundEpidermal growth factor receptor (EGFR) exon 20 insertion mutations account for 10% of all EGFR mutations and are mostly insensitive to approved EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Novel EGFR-TKIs have been developed or repurposed for these mutants. A limited number of preclinical studies have detailed these EGFR-TKIs. We sought to use commercially available mobocertinib (TAK-788) to characterize the preclinical therapeutic window of this EGFR-TKI against EGFR mutations and to probe possible on-target mechanisms of resistance (EGFR-C797S).MethodsWe used models of EGFR mutations to probe representative 1st, 2nd, 3rd generation, and in-development EGFR exon 20-active (poziotinib, mobocertinib) TKIs. We also introduced EGFR-C797S to these models to identify mechanisms of resistance.ResultsCells driven by the most common EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, H773_V774insH and others) were inhibited by in-development EGFR TKIs at doses below those affecting EGFR-wildtype; albeit more common EGFR mutations (exon 19 deletions and L858R) were inhibited more readily by mobocertinib and poziotinib. Mobocertinib was able to inhibit phosphorylation of EGFR in multiple preclinical models. The presence of EGFR-C797S led to >200-fold resistance in proliferation assays probing mobocertinib and osimertinib. Review of clinical studies of mobocertinib disclosed responses that could be lasting.ConclusionsThis is one of the initial reports to characterize the novel EGFR TKI mobocertinib and highlights its broad activity against EGFR mutants plus the therapeutic window to EGFR exon 20 insertion mutations; as well as EGFR-C797S as a possible mechanism of resistance. Further clinical development of mobocertinib merits continuation.

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