EGFR L858R + EGFR T790M

EAI045 was successfully labeled with tritium and carbon-11, and the in vivo results indicated [11C]EAI045 may be able to distinguish between mutated and non-mutated EGFR in non-small cell lung cancer mouse models. Cetuximab was hypothesized to increase EAI045 uptake; however, no significant effect was observed on the uptake of [11C]EAI045 in vivo or [3H]EAI045 in vitro in H1975 xenografts and cells.

Additionally, cell viability and apoptosis studies with lung cancer cells expressing the wild-type and double mutant proteins revealed that the WNWKV conjugate showed greater potency than the LARFFS conjugate, while LARFFS peptide alone showed poor binding to the kinase domain. Thus, we have designed peptide conjugates that show potential for further laboratory studies for developing therapeutics for targeting the EGFR receptor and its mutant T790M/L858R.

Significance Statement Drugs targeting EGFR kinase are commonly used to treat lung cancers but are affected by receptor dimerization. Here, we describe a locked kinase dimer that can be used to study EGFR inhibitor pharmacology.

Osimertinib was successfully labeled at two positions with carbon-11, yielding two EGFR PET tracers, [methylindole-C]osimertinib and [dimethylamine-C]osimertinib. The preclinical evaluation demonstrated uptake and retention in three NSCLC xenografts; A549, HCC827, and H1975. The highest uptake was observed in the primary Del19 EGFR mutated HCC827. The ability of [methylindole-C]osimertinib to distinguish between the T790M resistance mutated H1975 xenografts and the wild-type EGFR expressing A549 could not be confirmed in the ex vivo study.

This is the first study in which the risk of AC0010-induced cardiotoxicity was evaluated. In addition, novel multifunctional biosensors can comprehensively evaluate the antitumor efficacy and cardiotoxicity of drugs and candidate compounds.

Results of the present study further demonstrated that depletion or activation of EGFR/Akt signaling may regulate survivin expression though modulating ubiquitination. Collectively, these results suggested that DHM may act as a potential EGFR inhibitor, and may provide a novel choice of treatment strategy for patients with NSCLC.

In addition, docetaxel plus CKD-516 delayed tumor growth in-and extended the lifespan of-tumor-bearing mice. Thus, combination CKD-516 and docetaxel therapy could be used to treat EGFR-TKI-resistant NSCLC.

The performed analyses allowed us to identify two compounds 15 and 18 showing improved inhibition of double mutant EGFR with respect to the original hit, as well as interesting antiproliferative activity against H1975 NSCLC cancer cells expressing double mutant EGFR. The newly discovered compounds represent promising starting points for further hit-to-lead optimisation.

EGFR-T790M NSCLC cells promote TKI-sensitive NSCLC cell aggressiveness, at least partially, through mechanisms associated with EVs.

Interaction of Osimertinib with these residues is improved due to the T790M mutation which optimizes the ligand orientation for binding, as evident from the RMSD and the distances monitored. These results can provide guidance for the development of more selective 3rd generation EGFR TKIs.Communicated by Ramaswamy H. Sarma.

Clinicians should be alerted to the occurrence of gastric metastasis in lung cancer patients. Comprehensive evaluation and appropriate treatment for specific patients may improve the survival rate of GMLC patients.

Additionally, molecular docking analyses were performed to explain the action modes between the compounds and the corresponding EGFR kinases. In conclusion, compounds 9h and 22a have been demonstrated as promising candidates and worth further study.

We used four types of human lung cancer cell lines, including H1299 (epidermal growth factor receptor (EGFR) wild-type), PC9 (EGFR Glu746-Ala750 deletion mutation in exon 19; EGFR tyrosine kinase inhibitor (TKI)-sensitive), H1975 (EGFR L858R/T790M double-mutant; EGFR TKI-resistant), and PC9/ER (erlotinib-resistant) cells. EPP reversed hepatocyte growth factor (HGF)-induced MET phosphorylation and gefitinib resistance. Taken together, our results demonstrate that EPP exerted anticancer effects not only in EGFR TKI-sensitive NSCLC cells, but also in EGFR TKI-resistant NSCLC cells, by suppressing MET activity.

NSP-037 (18), an irreversible inhibitor of the L858R/T790M double-mutant EGFR (EGFR) using α-chlorofluoroacetamide (CFA) as a novel warhead, has seven times the inhibition selectivity for EGFR over the wild type (EGFR), as compared to clinically approved osimertinib (7)...Further, free energy decomposition analysis indicates that the electrostatic contribution of key residues plays an important role in the 18-bound complexes. QM/MM calculations show that the most favored mechanism for the Cys797 alkylation reaction is the direct displacement mechanism through a CFA-based inhibitor, producing a reaction with the lowest energy barrier and most stable product.

The level of YAP and pYAP was upregulated in osimertinib resistant xenograft tumors and residual tumor biopsies. Taken together, we identified PDK1 as a drug able target to treat osimertinib acquired resistance.

This signal seeking biomarker study using cfDNA to better understand the association of mutational status and the treatment efficacy of the combined treatment was feasible and informative despite the small-scale study, supporting the advantage of further implementation.

However, these osimertinib derivatives showed a significantly higher accumulation in lungs than in tumors. Therefore, for detecting the mutations in lung cancer, further structural modifications of the probes are required.

We also found that auranofin, an inhibitor of protein kinase C iota (PKCί), a protein upstream of ELF3, effectively induced cell death. (4) Our study suggests that blocking ELF3 is an effective way to induce cell death in NSCLC with K-Ras and EGFR T790M/L858R mutations and thus advocates the use of auranofin as an effective alternative drug to overcome EGFR TKI resistance.

Due to common development of drug resistance to first- and second-generation TKIs, third-generation inhibitors, including osimertinib and rociletinib, are developed. It is also demonstrated that these clones are able to retain their epigenetic differences through passaging orthotopically in mice and crucially that they have distinct drug vulnerabilities. This work serves as a blueprint for exploring how epigenetics can be used to stratify patients for precision medicine decisions.

Significant tumor growth inhibition in preclinical models was observed with this lead. 2019 Elsevier Ltd.

To overcome this resistance, 4-anilinoquinazoline-based irreversible inhibitors afatinib, dacomitinib has been developed...Among them, compounds 2i (IC 0.171 µM) and 11h (IC 0.159 µM) were identified as potent compounds, which displayed selective and potent anti-proliferative activity on gefitinib-resistant cell line NCI-H1975 as compared to the gefitinib and WZ4002 in cellular assay...The synthesized compounds were also evaluated for in vitro cytotoxic activity/hepatotoxicity against HepG2 cell line through MTT assay. The results revealed that compounds exhibited lower cytotoxicity to HepG2 cells.

Our functional studies found that the antitumor mechanisms of afatinib when combined with EA mainly occurred by inhibiting WNT/β-catenin pathway activation and suppression of the secretion of anti-inflammatory factors. These results revealed that combination of afatinib with EA derivatives not only provided a new therapeutic approach for EGFR/T790M-mutated NSCLC patients but also offered a new idea for developing new drugs or optimizing the dose of afatinib in clinical use in future antitumor therapy.

Although osimertinib has been approved to treat patients with T790M-positive NSCLC, the majority of patients will develop C797S mutation and suffer diseases again...The results showed that wighteone inhibited cell proliferation, suppressed EGFR signaling pathway, caused cell cycle redistribution and induced cell apoptosis. Our studies suggest that wighteone may provide a novel potential therapeutic strategy for NSCLC patients with T790M mutation.

Third-generation EGFR-TKIs, such as osimertinib and rociletinib (CO-1686), was developed to target such resistance mutations. Our results suggested that [Br]BrCO1686 has specificity toward NSCLC cells with double mutations EGFR L858R/T790M compared to those in EGFR L858R and wild-type EGFR. However, the in vivo accumulation of radioactivity in the targeted tumor needs to be optimized by structural modification.

In contrast, knockdown of 4E-BP1 showed the opposite effect and dramatically enhanced survivin protein level. Overall, our data indicate that targeting survivin might be an alternative strategy to sensitize EGFR-targeted therapy.

Our data suggest that Rab8 and Rabin8 mediate Muv formation through FGF secretion in the EGFR-TKI-resistant nematode model. Furthermore, FGFR-TKIs more effectively inhibit the growth of lung cancer cell lines in H1975 (EGFR T790M-L858R; EGFR-TKI-resistant) than H522 (wild-type EGFR) and H1650 (EGFR exon 19 deletion; EGFR-TKI-sensitive) cells, suggesting that FGFR-TKIs could be used to control cancers with EGFR-TKI-resistant mutations.

To promote open-source drug discovery, a tool has been developed, which incorporates the best performing models and allows users to predict the potential of chemical molecules as anti-TMLR inhibitor. It is expected that the machine learning classification models developed in this study will pave way for identifying novel inhibitors against the resistant EGFR double mutants.

Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC.

During the study, 2121 patients with EGFR mutation-positive NSCLC received first-generation (1G, gefitinib or erlotinib) or 2G EGFR-TKI (afatinib) as the first-line (1L) systemic therapy. The ORR, PFS and OS were poorer in patients with uncommon (especially other compound and other uncommon mutation) than those with common EGFR mutations. T790M was detected in 28.6% of the uncommon EGFR mutation-positive patients for whom prior 1G/2G EGFR-TKIs failed and underwent repeat biopsy at the time of progression.

We generated OR cell lines in-vitro as evidenced by increased drug resistance potential, increased mesenchymal features and enhanced autophagy activity. Development of Osimertinib resistance cells may serve as in-vitro model facilitating discovery of molecular aberration present during acquired mechanism of resistance.

Compound 27 also exhibited good microsomes stabilities in human, rat and mouse liver species, but low bioavailability. This work would be very useful for discovering new quinazoline derivatives as tyrosine kinase inhibitors targeting triple mutant L858R/T790M/C797S.

Intratumoral genetic heterogeneity of LACs was demonstrated associated with histological patterns. Heterogeneous PD-L1 expression in higher level usually occurred in solid component both in EGFR mutated and EGFR wild-typed LACs. EGFR mutated LACs heterogeneously had sensitizing and resistant mutation and was accompanied with PD-L1 expression, but discordant among histological constituents. Immune checkpoint inhibitor combined with third generation EGFR tyrosine kinase inhibitor should be more effective to these LACs.

Concomitant mutations were widespread in 19Del and L858R and were associated with poorer OR to EGFR-TKIs. However, 19Del and L858R had similar numbers and patterns of concomitant mutations, which might not explain the different sensitivity to EGFR-TKI.

The patient was treated with erlotinib 150mg daily as first-line treatment since 10 Aug, 2017 and achieved stable disease (SD) for 4 months...The patient received chemotherapy treatment consisting of pemetrexed and carboplatin for 4 cycles...Interestingly, sequencing at PD revealed the significant decrease in NOTCH2-NTRK1 fusion, suggesting the molecular efficacy of larotrectinib. The patient received 1 cycle of paclitaxel without benefit and shortly succumbed to the complications of metastatic disease with an overall survival of 21.5 months. In conclusion, our case suggested NOTCH2-NTRK1 could be another possible target of osimertinib resistance. Further research is needed to elucidate the mechanism.

One patient discontinued the drug because of drug-related interstitial pneumonitis. Osimertinib had favorable efficacy in the first-line treatment of metastatic NSCLC harboring activating EGFR mutations in ctDNA as well as tumor DNA.

Selective N-methylation of the H-bond accepting nitrogen ablates inhibitor potency, confirming the role of the K745 H-bond in potent, non-covalent inhibition of C797S variant. Insights from these studies offer new strategies for developing next generation inhibitors targeting EGFR in non-small cell lung cancer.

Afatinib treatment at 40 mg daily is associated with high rates of adverse events and dose reductions; alternative strategies including pulse intermittent dosing should be evaluated prospectively. Osimertinib (with favorable safety profile and intracranial penetration) has shown promising results in this population in a phase II trial from South Korea; additional trials are ongoing.

Approximately one fifth of EGFR-mutant patients harbor uncommon and compound mutations. Unlike those with exon19del/L858R, these patients-particularly those with baseline T790M mutations-show significantly inferior response rates to treatment (EGFR TKI or chemotherapy) and early disease progression.