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Metabolic reprogramming is widely known as a hallmark of cancer cells to allow adaptation of cells to sustain survival signals. In this report, we describe a novel oncogenic signaling pathway exclusively acting in mutated epidermal growth factor receptor (EGFR) non‐small cell lung cancer (NSCLC) with acquired tyrosine kinase inhibitor (TKI) resistance. Mutated EGFR mediates TKI resistance through regulation of the fatty acid synthase (FASN), which produces 16‐C saturated fatty acid palmitate. Our work shows that the persistent signaling by mutated EGFR in TKI‐resistant tumor cells relies on EGFR palmitoylation and can be targeted by Orlistat, an FDA‐approved anti‐obesity drug. Inhibition of FASN with Orlistat induces EGFR ubiquitination and abrogates EGFR mutant signaling, and reduces tumor growths both in culture systems and in vivo . Together, our data provide compelling evidence on the functional interrelationship between mutated EGFR and FASN and that the fatty acid metabolism pathway is a candidate target for acquired TKI‐resistant EGFR mutant NSCLC patients. Synopsis In EGFR mutated Non‐Small Cell Lung Carcinoma with acquired Tyrosine Kinase Inhibitors resistance, FASN mediates EGFR palmitoylation and supports tumor growth. With limited effective therapeutics, these data show that FASN is a candidate target for acquired TKI‐resistant EGFR mutant NSCLC. Identification of a positive feedback loop involving mutated EGFR and FASN in EGFR mutated NSCLC with acquired TKI resistance. FASN‐mediated EGFR palmitoylaton is crucial for survival of NSCLC cells, and influences its translocation to the nucleus. FASN inhibition suppresses tumor growth in both cell culture systems and in vivo models, highlighting its potential as a target for therapeutic intervention. Graphical Abstract In EGFR mutated Non‐Small Cell Lung Carcinoma with acquired Tyrosine Kinase Inhibitors resistance, FASN mediates EGFR palmitoylation and supports tumor growth. With limited effective therapeutics, these data show that FASN is a candidate target for acquired TKI‐resistant EGFR mutant NSCLC.

Differently from epidermal growth factor receptor (EGFR) 19Del and L858R mutations, the panoramic description of uncommon EGFR mutations is far from mature. Our understanding of its population characteristics, treatment response, and drug resistance mechanisms needs urgent expansion and deepening. Our study enrolled 437 patients with non–small‐cell lung cancer from four clinical centers and who had uncommon EGFR mutations. The clinical characteristics of all patients and the treatment outcomes of 190 advanced patients who received pharmacotherapy were analyzed. Moreover, the acquired resistance mechanisms were explored based on 53 tissue or liquid re‐biopsy data in 45 patients. Patients with EGFR 20ins had a shorter survival time compared with patients with non‐20ins mutations. In total, 149 cases had received EGFR‐tyrosine kinase inhibitors (TKI); afatinib was significantly superior to other EGFR‐TKIs both in ORR and mPFS in all uncommon mutations and especially in the L861Q group. The most common acquired drug resistance mechanism was MET amplification, followed by EGFR T790M, which was significantly different from common EGFR mutations. Uncommon EGFR mutation contained heterogeneous subtypes with limited data. We identified significantly worse efficacy of first‐generation EGFR‐TKIs than afatinib in L861Q; for the frequent application of first‐generation TKIs in the real world, this result deserves attention. For resistance mechanisms, the low incidence of T790M, but a high frequency of c‐MET amplification, in uncommon mutations differed from common mutations, especially when afatinib was applied. Our results complement the limited available data on uncommon mutations and provide valuable insights.

Emerging evidence has shown that exosomes derived from drug‐resistant tumour cells are able to horizontally transmit drug‐resistant phenotype to sensitive cells. However, whether exosomes shed by EGFR T790M‐mutant–resistant NSCLC cells could transfer drug resistance to sensitive cells has not been investigated. We isolated exosomes from the conditioned medium (CM) of T790M‐mutant NSCLC cell line H1975 and sensitive cell line PC9. The role and mechanism of exosomes in regulating gefitinib resistance was investigated both in vitro and in vivo. Exosome‐derived miRNA expression profiles from PC9 and H1975 were analysed by small RNA sequencing and confirmed by qRT‐PCR. We found that exosomes shed by H1975 could transfer gefitinib resistance to PC9 both in vitro and in vivo through activating PI3K/AKT signalling pathway. Small RNA sequencing and RT‐PCR confirmed that miR‐3648 and miR‐522‐3p were the two most differentially expressed miRNAs and functional study showed that up‐regulation of miR‐522‐3p could induce gefitinib resistance in PC9 cell. The findings of our study reveal an important mechanism of acquired resistance to EGFR‐TKIs in NSCLC.

With the wide clinical use of the third‐generation epidermal growth factor receptor (EGFR) inhibitor osimertinib for the treatment of EGFR‐mutated non–small cell lung cancer (NSCLC), acquired resistance caused by EGFR C797S tertiary mutation has become a concern. Therefore, fourth‐generation EGFR inhibitors that could overcome this mutation have gained increasing attention in recent years. Here, we identified LS‐106 as a novel EGFR inhibitor against C797S mutation and evaluated its antitumor activity both in vitro and in vivo. In cell‐free assay, LS‐106 potently inhibited the kinase activities of EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S with IC50 values of 2.4 nmol/L and 3.1 nmol/L, respectively, which was more potent than osimertinib. Meanwhile, LS‐106 exhibited comparable kinase inhibitory effect to osimertinib on EGFRL858R/T790M and wild‐type EGFR. Results from cellular experiments demonstrated that LS‐106 potently blocked the phosphorylation of EGFR C797S triple mutations in the constructed BaF3 cells that highly expressed EGFR19del/T790M/C797S or EGFRL858R/T790M/C797S, and thus inhibited the proliferation of these cells. We also constructed tumor cells harboring EGFR19del/T790M/C797S (named PC‐9‐OR cells) using the CRISPR/Cas9 system and found that LS‐106 markedly suppressed the activation of EGFR19del/T790M/C797S and the proliferation of PC‐9‐OR cells. Moreover, cells harboring EGFR19del/T790M/C797S underwent remarkable apoptosis upon LS‐106 treatment. In vivo experiments further demonstrated that oral administration of LS‐106 caused significant tumor regression in a PC‐9‐OR xenograft model, with a tumor growth inhibition rate (TGI) of 83.5% and 136.6% at doses of 30 and 60 mg/kg, respectively. Taken together, we identified LS‐106 as a novel fourth‐generation EGFR inhibitor against C797S mutation and confirmed its preclinical antitumor effects in C797S–triple‐mutant tumor models. In this study, we identified LS‐106 as a novel inhibitor against C797S–triple‐mutant epidermal growth factor receptor (EGFR) (EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S), which showed great in vitro and in vivo antitumor activity in EGFR‐C797S–triple‐mutant osimertinib‐resistant tumor models.

Third‐generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) is the standard therapy for patients harboring T790M after first‐generation EGFR‐TKI resistance. However, the impact of acquired EGFR amplification on the efficacy of third‐generation EGFR‐TKI against T790M remains uncertain. We aimed to investigate whether the presence of acquired EGFR amplification after first‐generation EGFR‐TKI resistance influences the efficacy of third‐generation EGFR‐TKI in patients with advanced non‐small‐cell lung cancer (NSCLC). We reviewed data from 275 advanced NSCLC patients harboring T790M after first‐generation EGFR‐TKI resistance. Patients were categorized into two groups based on the presence or absence of acquired EGFR amplification identified through next‐generation sequencing (NGS) after first‐line EGFR‐TKI treatment. We evaluated the efficacy of osimertinib used as a second‐line treatment. Among these patients, 59 exhibited acquired EGFR amplification, while 216 did not. The median progression‐free survival (PFS) was 12.20 months in the EGFR amplification group and 12.03 months in the non‐amplification group (p = 0.011), with median overall survival (OS) of 33.90 months and 23.30 months, respectively (p = 0.164). Multivariate analysis of PFS revealed that acquired EGFR amplification and EGFR 19del were independent prognostic factors for patients with T790M undergoing osimertinib. Additionally, subgroup analysis indicated a prolonged PFS in patients with EGFR 19del compared to those with EGFR 21L858R (p = 0.034) in the EGFR amplification group. Following first‐generation EGFR‐TKI resistance, advanced EGFR‐mutant NSCLC patients harboring both acquired T790M and EGFR amplification are likely to experience enhanced PFS with osimertinib. This phenomenon is particularly noteworthy among individuals with EGFR 19del. Acquired EGFR amplification may coincide with T790M after first‐generation EGFR‐TKI resistance, accounting for 21.5% of cases in our study. Patients with both acquired T790M and EGFR amplification after first‐generation EGFR‐TKI may derive enhanced benefits from 3rd EGFR‐TKI. Patients with both acquired T790M and EGFR amplification, particularly those with EGFR 19del, exhibited a longer PFS.

Patients with epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer (NSCLC) harboring BIM deletion polymorphism (BIM deletion) have poor responses to EGFR TKI. Mechanistically, the BIM deletion induces preferential splicing of the non‐functional exon 3‐containing isoform over the functional exon 4‐containing isoform, impairing TKI‐induced, BIM‐dependent apoptosis. Histone deacetylase inhibitor, vorinostat, resensitizes BIM deletion‐containing NSCLC cells to EGFR‐TKI. In the present study, we determined the safety of vorinostat‐gefitinib combination and evaluated pharmacodynamic biomarkers of vorinostat activity. Patients with EGFR‐mutated NSCLC with the BIM deletion, pretreated with EGFR‐TKI and chemotherapy, were recruited. Vorinostat (200, 300, 400 mg) was given daily on days 1‐7, and gefitinib 250 mg was given daily on days 1‐14. Vorinostat doses were escalated based on a conventional 3 + 3 design. Pharmacodynamic markers were measured using PBMC collected at baseline and 4 hours after vorinostat dose on day 2 in cycle 1. No dose‐limiting toxicities (DLT) were observed in 12 patients. We determined 400 mg vorinostat as the recommended phase II dose (RP2D). Median progression‐free survival was 5.2 months (95% CI: 1.4‐15.7). Disease control rate at 6 weeks was 83.3% (10/12). Vorinostat preferentially induced BIM mRNA‐containing exon 4 over mRNA‐containing exon 3, acetylated histone H3 protein, and proapoptotic BIMEL protein in 11/11, 10/11, and 5/11 patients, respectively. These data indicate that RP2D was 400 mg vorinostat combined with gefitinib in BIM deletion/EGFR mutation double‐positive NSCLC. BIM mRNA exon 3/exon 4 ratio in PBMC may be a useful pharmacodynamic marker for treatment. Vorinostat, in combination with gefitinib, induced acetylated histone H3 protein expression, as well as a decrease in the BIM mRNA exon 3/exon 4 ratio in PBMC from BIM deletion polymorphism/EGFR mutation double‐positive NSCLC patients. These results provide proof of concept that the combined therapy can mitigate the functional effects of BIM deletion polymorphism.

Patient‐derived xenograft (PDX) models are a useful tool in cancer biology research. However, the number of lung cancer PDX is limited. In the present study, we successfully established 10 PDX, including three adenocarcinoma (AD), six squamous cell carcinoma (SQ) and one large cell carcinoma (LA), from 30 patients with non‐small cell lung cancer (NSCLC) (18 AD, 10 SQ, and 2 LA), mainly in SCID hairless outbred (SHO) mice (Crlj:SHO‐PrkdcscidHrhr). Histology of SQ, advanced clinical stage (III‐IV), status of lymph node metastasis (N2‐3), and maximum standardized uptake value ≥10 when evaluated using a delayed 18F‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography (FDG‐PET) scan was associated with successful PDX establishment. Histological analyses showed that PDX had histology similar to that of patients’ surgically resected tumors (SRT), whereas components of the microenvironment were replaced with murine cells after several passages. Next‐generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had epidermal growth factor receptor (EGFR) mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors (EGFR‐TKI), such as gefitinib and osimertinib. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced that was associated with epithelial‐to‐mesenchymal transition. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR‐TKI resistance. We successfully established 10 PDX. Next‐generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had EGFR mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR‐TKI resistance.

Acquired T790 M mutation is the commonest cause of resistance for advanced non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) mutant patients who had progressed after first line EGFR TKI (tyrosine kinase inhibitor). Several third generation EGFR TKIs which are EGFR mutant selective and wild-type (WT) sparing were developed to treat these patients with T790 M acquired resistant mutation. Osimertinib is one of the third generation EGFR TKIs and is currently the most advanced in clinical development. Unfortunately, despite good initial response, patients who was treated with third generation EGFR TKI would develop acquired resistance and several mechanisms had been identified and the commonest being C797S mutation at exon 20. Several novel treatment options were being developed for patients who had progressed on third generation EGFR TKI but they are still in the early phase of development. Osimertinib under FLAURA study had been shown to have better progression-free survival over first generation EGFR TKI in the first line setting and likely will become the new standard of care.

The genomic instability associated with cancer can result in the formation of extrachromosomal circular DNA (eccDNA), which contributes to tumor heterogeneity, gene amplification, tumor evolution, and drug resistance. However, most studies on eccDNA have been conducted on tumor tissue or cancer cell lines, and limited research has been done on eccDNA in plasma. In this study, we investigated eccDNA in non‐small cell lung cancer (NSCLC) by sequencing plasma eccDNA from 32 epidermal growth factor receptor ( EGFR )‐mutated NSCLC patients before and during treatment with osimertinib, as well as plasma eccDNA from five healthy individuals. Plasma eccDNA was identified in all samples but with significantly higher levels in cancer patients than healthy controls. EGFR ‐overlapping eccDNA, eccDNA that contains part of or the whole EGFR gene, was detected in the majority of samples both at baseline and during treatment. High levels of EGFR ‐overlapping eccDNA during osimertinib treatment were associated with significantly shorter progression‐free survival and overall survival. Plasma eccDNA represents a newly identified type of biomarker for monitoring treatment efficacy.

Son of sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic receptor tyrosine kinase (RTK)‐dependent RAS activation. Here, we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR tyrosine kinase inhibitor (EGFR‐TKI) osimertinib in lung adenocarcinoma (LUAD). SOS2 deletion (SOS2KO) sensitized EGFR‐mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit phosphatidylinositol 3‐kinase (PI3K)/AKT pathway activation, oncogenic transformation, and survival. Bypassing RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR‐TKIs; SOS2KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET‐driven bypass model, SOS2KO inhibited hepatocyte growth factor (HGF)‐stimulated PI3K signaling to block HGF‐driven osimertinib resistance. Using a long‐term in situ resistance assay, most osimertinib‐resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT‐dependent osimertinib resistance was markedly reduced by SOS2 deletion; the few SOS2KO cultures that became osimertinib resistant primarily underwent non‐RTK‐dependent epithelial–mesenchymal transition (EMT). Since bypassing RTK reactivation and/or tertiary EGFR mutations represent most osimertinib‐resistant cancers, these data suggest that targeting proximal RTK signaling, here exemplified by SOS2 deletion, has the potential to delay the development osimertinib resistance and enhance overall clinical responses for patients with EGFR‐mutated LUAD. RTK‐dependent PI3K/AKT activation, associated with a hybrid epithelial/mesenchymal phenotype, is a hallmark of EGFR‐TKI‐resistant lung adenocarcinoma (LUAD). This study shows that SOS2 deletion reduces the threshold for PI3K/AKT inhibition, effectively reducing the frequency of RTK/AKT‐pathway‐driven EGFR‐TKI‐resistant cultures. These findings suggest that proximal RTK pathway inhibition has the potential to enhance clinical responses for patients with EGFR‐mutated LUAD.