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Epidermal growth factor receptor‐targeted (EGFR‐targeted) therapies show promise for non‐small cell lung cancer (NSCLC), but they are ineffective in a third of patients who lack EGFR mutations. This underlines the need for personalized treatments for patients with EGFR wild‐type NSCLC. A genome‐wide CRISPR/Cas9 screen has identified the enzyme phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), which is vital in de novo purine biosynthesis and tumor development, as a potential drug target for EGFR wild‐type NSCLC. We have further confirmed that PAICS expression is significantly increased in NSCLC tissues and correlates with poor patient prognosis. Knockdown of PAICS resulted in a marked reduction in both in vitro and in vivo proliferation of EGFR wild‐type NSCLC cells. Additionally, PAICS silencing led to cell‐cycle arrest in these cells, with genes involved in the cell cycle pathway being differentially expressed. Consistently, an increase in cell proliferation ability and colony number was observed in cells with upregulated PAICS in EGFR wild‐type NSCLC. PAICS silencing also caused DNA damage and cell‐cycle arrest by interacting with DNA repair genes. Moreover, decreased IMPDH2 activity and activated PI3K–AKT signaling were observed in NSCLC cells with EGFR mutations, which may compromise the effectiveness of PAICS knockdown. Therefore, PAICS plays an oncogenic role in EGFR wild‐type NSCLC and represents a potential therapeutic target for this disease. Genome‐wide CRISPR–Cas9 screening identified PAICS as a potential target for EGFR wild‐type NSCLC. Increased PAICS expression in NSCLC tissues correlates with poor prognosis. PAICS knockdown markedly reduces in vitro and in vivo proliferation of EGFR wild‐type NSCLC cells, inducing cell‐cycle arrest through interaction with DNA repair genes. This highlights PAICS as an oncogenic factor and a potential therapeutic target for EGFR wild‐type NSCLC.

Background Epidermal growth factor receptor (EGFR)-mutated lung cancer constitutes a major subgroup of non-small cell lung cancer (NSCLC) and osimertinib is administrated as first-line treatment. However, most patients with osimertinib treatment eventually relapse within one year. The underlying mechanisms of osimertinib resistance remain largely unexplored. Methods Exosomes isolation was performed by differential centrifugation. Co-culture assays were conducted to explore the alteration of drug sensitivity by cell viability and apoptosis assays. Immunofluorescence and flow cytometry were performed to visualize the formation or absorption of exosomes. Exosomes secretion was measured by Nanoparticle Tracking Analysis or ELISA. The xenograft tumor model in mice was established to evaluate the effect of exosomes on osimertinib sensitivity in vivo. Results Intercellular transfer of exosomal wild type EGFR protein confers osimertinib resistance to EGFR-mutated sensitive cancer cells in vitro and in vivo. Co-culture of EGFR-mutated sensitive cells and EGFR-nonmutated resistant cells promoted osimertinib resistance phenotype in EGFR-mutated cancer cells, while depletion of exosomes from conditioned medium or blockade of exosomal EGFR by neutralizing antibody alleviated this phenotype. Mechanistically, osimertinib promoted the release of exosomes by upregulated a Rab GTPase (RAB17). Knockdown of RAB17 resulted in the decrease of exosomes secretion. Moreover, exosomes could be internalized by EGFR-mutated cancer cells via Clathrin-dependent endocytosis and then the encapsulated exosomal wild type EGFR protein activated downstream PI3K/AKT and MAPK signaling pathways and triggered osimertinib resistance. Conclusions Intercellular transfer of exosomal wild type EGFR promotes osimertinib resistance in NSCLC, which may represent a novel resistant mechanism of osimertinib and provide a proof of concept for targeting exosomes to prevent and reverse the osimertinib resistance.

Background The landscape of non-small cell lung cancer (NSCLC) therapy is rapidly changing. This analysis aimed to understand patient characteristics, diagnosis and treatment patterns in patients with metastatic NSCLC (mNSCLC) without EGFR and ALK mutations across five European countries. Methods Data were drawn from the Adelphi NSCLC Disease Specific Programme™, a point-in-time survey of oncologists/pulmonologists and their consulting patients in France, Germany, Italy, Spain and UK. Physicians completed record forms (RFs) for the next six consecutive consulting patients with advanced NSCLC, who then voluntarily completed questionnaires. As an oversample, physicians provided a further ten RFs specifically for patients with EGFR -wild-type mNSCLC: five patients diagnosed before March 2020 (pre-SARS-CoV-2 [COVID-19]) and five patients diagnosed from March 2020 (during COVID-19). Only EGFR -wild-type/ ALK -wild-type patients were included for analysis. Results Mean (standard deviation [SD]) age for 1073 patients with EGFR -wild-type/ ALK -wild-type mNSCLC was 66.2 (8.9) years, 65.2% were male and 63.7% had adenocarcinoma. Level of PD-L1 expression at advanced diagnosis was < 1% for 23.1% of patients, 1–49% for 40.9% and ≥ 50% for 36.0%. Most common first-line (1L) advanced treatment was chemotherapy only (36.9%), immunotherapy monotherapy (30.5%) or immunotherapy + chemotherapy (27.6%). Of 158 patients who had progressed beyond 1L therapy, the mean (SD) time-to-treatment discontinuation was 5.1 (4.3) months; 75.9% of whom completed their 1L treatment as intended. A complete response was achieved by 6.7% and a partial response by 69.2% of patients. Of 38 patients who discontinued 1L treatment early, disease progression was reported for 73.7%. Quality of life (QoL) reported by patients was generally lower than normative reference values. Of 2373 oversample patients, physicians reported management changes for 34.7% due to COVID-19, ranging from 19.6% in Germany to 79.7% in the UK. Immunotherapy was prescribed as 1L NSCLC treatment during COVID-19 for 64.2% ( n  = 786) of patients and pre-COVID-19, for 47.8% ( n  = 549). Conclusions Real-world treatment patterns suggest that chemotherapy use remains high despite guidelines recommending immunotherapy-based 1L treatment for mNSCLC. QoL reported by patients was generally lower than population reference values. Not implying causality, 1L immunotherapy use was higher during COVID-19 than pre-COVID-19, and the UK saw the biggest impact to patient management due to COVID-19.

Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung cancer patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type EGFR tumors has been shown to be marginal. Methods that can sensitize EGFR-TKIs to EGFR wild-type NSCLC remain rare. Hence, we determined whether combination treatment can maximize the therapeutic efficacy of EGFR-TKIs. Methods We established a focused drug screening system to investigate candidates for overcoming the intrinsic resistance of wild-type EGFR NSCLC to EGFR-TKIs. Molecular docking assays and western blotting were used to identify the binding mode and blocking effect of the candidate compounds. Proliferation assays, analyses of drug interactions, colony formation assays, flow cytometry and nude mice xenograft models were used to determine the effects and investigate the molecular mechanism of the combination treatment. Results Betulinic acid (BA) is effective at targeting EGFR and synergizes with EGFR-TKIs (gefitinib and osimertinib) preferentially against wild-type EGFR. BA showed inhibitory activity due to its interaction with the ATP-binding pocket of EGFR and dramatically enhanced the suppressive effects of EGFR-TKIs by blocking EGFR and modulating the EGFR-ATK-mTOR axis. Mechanistic studies revealed that the combination strategy activated EGFR-induced autophagic cell death and that the EGFR-AKT-mTOR signaling pathway was essential for completing autophagy and cell cycle arrest. Activation of the mTOR pathway or blockade of autophagy by specific chemical agents markedly attenuated the effect of cell cycle arrest. In vivo administration of the combination treatment caused marked tumor regression in the A549 xenografts. Conclusions BA is a potential wild-type EGFR inhibitor that plays a critical role in sensitizing EGFR-TKI activity. BA combined with an EGFR-TKI effectively suppressed the proliferation and survival of intrinsically resistant lung cancer cells via the inhibition of EGFR as well as the induction of autophagy-related cell death, indicating that BA combined with an EGFR-TKI may be a potential therapeutic strategy for overcoming the primary resistance of wild-type EGFR-positive lung cancers. Graphical abstract Highlights 1. BA is a potent wild-type EGFR inhibitor. 2. BA enhances the anticancer efficacy of erlotinib/gefitinib in NSCLC patients with wild-type EGFR. 3. The combination of BA and gefitinib/osimertinib synergistically blocks EGFR and inhibits the PI3K-AKT-mTOR signaling pathway, leading to autophagic cell death and cell cycle arrest. 4. This combination strategy targets wild-type EGFR in NSCLC and induces autophagy and tumor suppression in vivo. BA, an EGFR inhibitor, sensitizes EGFR-TKIs’ activity, indicating that BA plus EGFR-TKIs may be a potential therapeutic strategy to overcome the primary resistance of wild-type EGFR NSCLC.

Background Lycorine has been revealed to inhibit the development of many kinds of malignant tumors, including glioblastoma multiforme (GBM). Although compelling evidences demonstrated Lycorine’s inhibition on cancers through some peripheral mechanism, in-depth mechanism studies of Lycotine’s anti-GBM effects still call for further exploration. Epidermal Growth Factor Receptor (EGFR) gene amplification and mutations are the most common oncogenic events in GBM. Targeting EGFR by small molecular inhibitors is a rational strategy for GBM treatment. Methods The molecular docking modeling and in vitro EGFR kinase activity system were employed to identify the potential inhibitory effects of Lycorine on EGFR. And the Biacore assay was used to confirm the direct binding status between Lycorine and the intracellular EGFR (696–1022) domain. In vitro assays were conducted to test the suppression of Lycorine on the biological behavior of GBM cells. By RNA interference, EGFR expression was reduced then cells underwent proliferation assay to investigate whether Lycorine’s inhibition on GBM cells was EGFR-dependent or not. RT-PCR and western blotting analysis were carried out to investigate the underlined molecular mechanism that Lycorine exerted on EGFR itself and EGFR signaling pathway. Three different xenograft models (an U251-luc intracranially orthotopic transplantation model, an EGFR stably knockdown U251 subcutaneous xenograft model and a patient-derived xenograft model) were performed to verify Lycorine’s therapeutic potential on GBM in vivo. Results We identified a novel small natural molecule Lycorine binding to the intracellular EGFR (696–1022) domain as an inhibitor of EGFR. Lycorine decreased GBM cell proliferation, migration and colony formation by inducing cell apoptosis in an EGFR-mediated manner. Furthermore, Lycorine inhibited the xenograft tumor growths in three animal models in vivo. Besides, Lycorine impaired the phosphorylation of EGFR, AKT, which were mechanistically associated with expression alteration of a series of cell survival and death regulators and metastasis-related MMP9 protein. Conclusions Our findings identify Lycorine directly interacts with EGFR and inhibits EGFR activation. The most significant result is that Lycorine displays satisfactory therapeutic effect in our patient-derived GBM tumor xenograft, thus supporting the conclusion that Lycorine may be considered as a promising candidate in clinical therapy for GBM.

Background The prognostic value of cytokeratin 19 fragment (CYFRA 21 − 1) and Ki67 in advanced non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor (EGFR) remains to be explored. Methods In this study, 983 primary NSCLC patients from January 2016 to December 2019 were retrospectively reviewed. Finally, 117 advanced NSCLC patients with wild-type EGFR and 37 patients with EGFR mutation were included and prognostic value of CYFRA 21 − 1 and Ki67 were also identified. Results The patients age, smoking history and the Eastern Corporative Oncology Group (ECOG) performance scores were significantly different between CYFRA21-1 positive and negative groups ( p  < 0.05), while no significant differences were found in Ki67 high and low groups. The results of over survival (OS) demonstrated that patients with CYFRA21-1 positive had markedly shorter survival time than CYFRA21-1 negative ( p  < 0.001, For whole cohorts; p  = 0.002, For wild-type EGFR). Besides, patients with wild-type EGFR also had shorter survival times than Ki67 high group. Moreover, In CYFRA 21 − 1 positive group, patients with Ki67 high had obviously shorter survival time compared to patients with Ki67 low (median: 24vs23.5 months; p  = 0.048). However, Ki67 could not be used as an adverse risk factor for patients with EGFR mutation. Multivariate cox analysis showed that age (HR, 1.031; 95%CI, 1.003 ~ 1.006; p  = 0.028), Histopathology (HR, 1.760; 95%CI,1.152 ~ 2.690; p  = 0.009), CYFRA 21 − 1 (HR, 2.304; 95%CI,1.224 ~ 4.335; p  = 0.01) and Ki67 (HR, 2.130; 95%CI,1.242 ~ 3.652; p  = 0.006) served as independent prognostic risk factor for advanced NSCLC patients. Conclusions Our finding indicated that CYFRA 21 − 1 was an independent prognostic factor for advanced NSCLC patients and Ki67 status could be a risk stratification marker for CYFRA 21 − 1 positive NSCLC patients with wild-type EGFR.

Inhibiting the tyrosine kinase activity of epidermal growth factor receptor (EGFR) using small-molecule tyrosine kinase inhibitors (TKIs) or monoclonal antibodies is often ineffective in treating cancers harboring wild-type EGFR. Given the fact that EGFR possesses a kinase-independent pro-survival function, more effective inhibition of EGFR-mediated signals is therefore necessary. In this study, we investigated the effects of using a combination of low-dose nimotuzumab and theasinensin A to evaluate whether the inhibitory effect of nimotuzumab on NCI-H441 cancer cells was enhanced. Here, theasinensin A, a novel epigallocatechin-3-gallate (EGCG) derivative, was identified and its potent anticancer activity against wild-type EGFR NSCLC was demonstrated in vitro; the anticancer activity was induced through degradation of EGFR. Mechanistic studies further revealed that theasinensin A bound directly to the EGFR extracellular domain, which decreased interaction with its ligand EGF in combination with nimotuzumab. Theasinensin A significantly promoted EGFR degradation and repressed downstream survival pathways in combination with nimotuzumab. Meanwhile, treatment with theasinensin A and nimotuzumab prevented xenograft growth, whereas the single agents had limited effect. Thus, the combination therapy of theasinensin A with nimotuzumab is a powerful candidate for treatment of wild-type EGFR cancers.

Background Bevacizumab (Avastin ® ) is a monoclonal antibody targeting the vascular endothelial growth factor (VEGF). Used alone or in combination with chemotherapy and/or immunotherapy, Avastin ® has shown promising efficacy in many cancers. This study compared the efficacy and safety of TAB008 with Avastin ® sourced from the EU (bevacizumab-EU), in patients with non-squamous non-small cell lung cancer (nsNSCLC). Method In this randomized, double-blind, multicenter, phase III similarity study, treatment naïve for metastatic lung cancer., EGFR wild-type, locally advanced, metastatic, or recurrent non-squamous, non-small cell, lung cancer (nsNSCLC) patients were enrolled and randomized (1:1) into TAB008 or Avastin ® groups. Patients received TAB008 or Avastin ® 15 mg/kg intravenously plus paclitaxel/carboplatin for 4–6 cycles followed by TAB008 or Avastin ® 7.5 mg/kg until disease progression, unacceptable toxicity or death. The primary endpoint compared the objective response rate (ORR) within 6 cycles as read by an independent radiological review committee (IRRC). Secondary endpoints compared disease control rate (DCR) Within 6 cycles, duration of response (DoR), progression-free survival (PFS), a year overall survival rate (OSR), overall survival (OS), safety, immunogenicity, and steady-state pharmacokinetics. Results A total of 549 nsNSCLC patients were enrolled (277 in TAB008 group and 272 in Avastin ® group). In the full analysis set, ORRs were 55.957% for TAB008 and 55.720% for Avastin ® , and the ORR ratio was 1 (90% CI 0.89–1.14), well within the predefined equivalence margin of 0.75–1.33. No significant differences were found in DCR within 6 cycles (95.703% vs 95.367%, p  = 0.8536), DoR (8.17 vs 7.3 months, p  = 0.3526), PFS (9.10 vs. 7.97 months, p  = 0.9457), 1 year overall survival rate (66.2% vs 68%, p  = 0.6793), or OS (20.4 vs 17.6 months, p  = 0.6549). Serious adverse events (SAEs) occurred in 37.55% (104/277) of patients in the TAB008 group and 34.32% (93/271) in the Avastin ® group. Anti-drug antibodies were reported in 3 of 277 (1.08%) TAB008 patients, and 5 of 271 (1.85%) Avastin ® patients, neutralizing antibody (Nab) was positive in 1 patient on Avastin ® , which became negative upon follow-up. The steady-state trough concentrations ( C ssmin ) were 106.13 μg/mL in TAB008 group and 96.03 μg/mL in Avastin ® groups, with the treatment group ratio of LS geometric means fully contained within the bioequivalence limits of 80.00–125.00% (90% CI was 101.74–120.05%). Conclusions TAB008 is similar to Avastin ® in terms of efficacy, safety, and pharmacokinetic parameters, with comparable immunogenicity. Trial registration ClinicalTrials.gov number; NCT05427305.

To identify whether PD-L1 expression and EGFR status are associated with response to treatment benefit in advanced non-small-cell lung cancer (NSCLC) patients receiving PD-1/PD-L1 inhibitors. The relevant studies were retrieved and systematic evaluation was conducted. Databases were searched until November 2018. A total of 12 randomized controlled trials (RCTs) with 6932 patients were included. Patients with the higher PD-L1 expression level tend to have a longer progression-free survival (PFS), overall survival (OS) and overall response rate (ORR). PFS and OS were significantly prolonged in all the subgroups of PD-L1 expression levels. For patients with PD-L1 expression levels of ≥1%, overall response rates were significantly prolonged, but there was no difference in patients with PD-L1 expression levels of <1% (hazard ratio [HR]: 1.75; 95% CI: 0.87–3.52; p = 0.12). EGFR wild-type NSCLC patients could benefit from PD-1/PD-L1 inhibitors in PFS (HR: 0.65; 95% CI: 0.45–0.91; p = 0.01) and OS (HR: 0.67; 95% CI: 0.62–0.73; p < 0.00001). This study indicates that PD-L1-positive or EGFR wild-type advanced NSCLC patients might get potential benefit from PD-1/PD-L1 inhibitors.

Background Docetaxel, pemetrexed, erlotinib, and gefitinib are recommended as second-line treatment for advanced non-small cell lung cancer (NSCLC) with wild-type or unknown status for epidermal growth factor receptor (EGFR). However, the number of published randomized clinical trials (RCTs) on this topic is increasing. Our objective was to assess the comparative effectiveness and tolerability of all second-line treatments for advanced NSCLC with wild-type or unknown status for EGFR by a systematic review and network meta-analysis. Methods MEDLINE, EMBASE, CENTRAL, ClinicalTrials.gov, and the US Food and Drug Administration website, as well as other sources, were searched for available reports up to June 6, 2017. Two reviewers independently selected published and unpublished reports of RCTs comparing any second-line treatments, extracted data and assessed the risk of bias of all included trials. We performed a Bayesian network meta-analysis. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes included objective response (ObR), the number of serious adverse events, and quality of life. Results We included 102 RCTs involving 36,058 patients (62% male, median age 61 years, 81% with stage IV cancer, 80% smokers, and 92% with performance status 0–1). We revealed a differential reporting of outcomes between efficacy and safety outcomes. Half of the trials reported safety outcomes and less than 20% quality of life. For OS, nivolumab was more effective than docetaxel (hazard ratio (HR) 0.69, 95% credible interval (CrI) 0.56–0.83), pemetrexed (0.67, 0.52–0.83), erlotinib (0.68, 0.53–0.86), and gefitinib (0.66, 0.53–0.83). Pembrolizumab, atezolizumab, and pemetrexed plus erlotinib were also significantly more effective than docetaxel, pemetrexed, erlotinib, and gefitinib. For PFS, erlotinib plus cabozantinib was more effective than docetaxel (HR 0.39, 95% CrI 0.18–0.84), pemetrexed (0.38, 0.18–0.82), erlotinib (0.37, 0.18–0.78), and gefitinib (0.38, 0.18–0.82). Cabozantinib and pemetrexed plus erlotinib were also significantly more effective than the four recommended treatments. For ObR, no treatment was significantly more effective. The effectiveness of the four recommended treatments was similar and they were ranked among the 25 less-effective treatments. For safety, evidence is insufficient to draw certain conclusions. Conclusions Nivolumab, pembrolizumab, atezolizumab, and pemetrexed plus erlotinib may be the most effective second-line treatments for NSCLC in terms of OS. The four recommended treatments seem to have relatively poor performance. However, the impact on life expectancy of immunotherapy versus other treatments should be further explored by future analyses, and more trials comparing the novel treatments are needed to reduce uncertainty in these results. Trial registration Registration number: PROSPERO ( CRD42015017592 )