News - EGFR mutation + EGFR T790M + EGFR C797S

over2years

Design, synthesis and biological evaluation of novel osimertinib derivatives as reversible EGFR kinase inhibitors. (PubMed, Eur J Med Chem)

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.

over 2 years ago

Journal

EGFR (Epidermal growth factor receptor) • MET (MET proto-oncogene, receptor tyrosine kinase)

EGFR mutation • EGFR L858R • EGFR T790M • EGFR C797S • EGFR L858R + EGFR T790M • EGFR T790M + EGFR C797S • EGFR H1975 • EGFR mutation + EGFR T790M + EGFR C797S

Tagrisso (osimertinib)

4years

Phase 1 Study of the Efficacy and Safety of Ramucirumab in Combination with Osimertinib in Advanced T790M-Positive EGFR-Mutant Non-Small Cell Lung Cancer. (PubMed, Clin Cancer Res)

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

4 years ago

Clinical • P1 data • Journal • Combination therapy

EGFR (Epidermal growth factor receptor) • KDR (Kinase insert domain receptor)

EGFR mutation • EGFR L858R • EGFR exon 19 deletion • MET amplification • EGFR T790M • EGFR amplification • EGFR C797S • EGFR L858R + EGFR T790M • EGFR C797S + EGFR T790M + EGFR L858R • EGFR C797S + EGFR T790M + EGFR exon 19 deletion • EGFR positive • MET amplification + EGFR mutation • EGFR T790M + EGFR C797S • EGFR exon 2-7 deletion + EGFR amplification • EGFR mutation + EGFR T790M • EGFR exon 19 deletion + MET amplification • EGFR mutation + EGFR T790M + EGFR C797S • EGFR T790M + exon 19 deletion

Tagrisso (osimertinib)

4years

Design, Synthesis and Biological Evaluation of the Quinazoline Derivatives as L858R/T790M/C797S Triple Mutant Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors. (PubMed, Chem Pharm Bull (Tokyo))

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.

4 years ago

Journal

EGFR (Epidermal growth factor receptor)

EGFR mutation • EGFR L858R • EGFR T790M • EGFR C797S • EGFR L858R + EGFR T790M • EGFR C797S + EGFR T790M + EGFR L858R • EGFR T790M + EGFR C797S • EGFR H1975 • EGFR mutation + EGFR T790M • EGFR mutation + EGFR T790M + EGFR C797S

4years

Structural Basis for EGFR Mutant Inhibition by Trisubstituted Imidazole Inhibitors. (PubMed, J Med Chem)

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.

4 years ago

Journal

EGFR (Epidermal growth factor receptor)

EGFR mutation • EGFR L858R • EGFR T790M • EGFR C797S • EGFR L858R + EGFR T790M • EGFR C797S + EGFR T790M + EGFR L858R • EGFR T790M + EGFR C797S • EGFR mutation + EGFR T790M • EGFR mutation + EGFR T790M + EGFR C797S

4years

CH7233163 overcomes osimertinib resistant EGFR-Del19/T790M/C797S mutation. (PubMed, Mol Cancer Ther)

Furthermore, crystal structure analysis suggested that CH7233163 is a non-covalent ATP competitive inhibitor for EGFR-Del19/T790M/C797S that utilizes multiple interactions with the EGFR's αC-helix-in conformation to achieve potent inhibitory activity and mutant selectivity. Therefore, we conclude that CH7233163 is a potentially effective therapy for osimertinib resistant patients, especially in cases of EGFR-Del19/T790M/C797S.

4 years ago

Journal

EGFR (Epidermal growth factor receptor)

Tagrisso (osimertinib) • CH7233163

4years

Notch inhibition overcomes resistance to Tyrosine Kinase Inhibitors in EGFR-driven lung adenocarcinoma. (PubMed, J Clin Invest)

EGFR-mutated lung adenocarcinoma patients treated with gefitinib and osimertinib show a therapeutic benefit limited by the appearance of secondary mutations, such as EGFRT790M and EGFRC797S. Finally, in patients with EGFR mutations treated with tyrosine kinase inhibitors, HES1 protein levels increased during relapse and correlated with shorter progression-free survival. Therefore, our results offer a proof of concept for an alternative treatment to chemotherapy in lung adenocarcinoma osimertinib treated patients after disease progression.

4 years ago

Journal

EGFR (Epidermal growth factor receptor) • STAT3 (Signal Transducer And Activator Of Transcription 3) • HES1 (Hes Family BHLH Transcription Factor 1)

EGFR mutation • EGFR T790M • EGFR C797S • EGFR mutation + EGFR T790M • EGFR mutation + EGFR T790M + EGFR C797S

Tagrisso (osimertinib) • gefitinib

over4years

Interaction and molecular dynamics simulation study of Osimertinib (AstraZeneca 9291) anticancer drug with the EGFR kinase domain in native protein and mutated L844V and C797S. (PubMed, J Cell Biochem)

According to our computational simulation, the results supported the experimental models and, therefore, could confirm and predict the molecular mechanism of drug efficacy.

over 4 years ago

Journal

EGFR (Epidermal growth factor receptor)

EGFR mutation • EGFR L858R • EGFR T790M • EGFR C797S • EGFR L858R + EGFR T790M • EGFR C797S + EGFR T790M + EGFR L858R • EGFR L718Q • EGFR mutation + EGFR T790M • EGFR mutation + EGFR T790M + EGFR C797S

Tagrisso (osimertinib)

over4years

Acquired resistance to osimertinib in patients with non-small-cell lung cancer: mechanisms and clinical outcomes. (PubMed, J Cancer Res Clin Oncol)

The study revealed heterogeneous mechanisms of resistance to osimertinib in advanced NSCLC patients and their association with clinical outcomes. Patients who maintained T790M mutation or with EGFR-dependent resistance mechanism had longer clinical outcome benefits.

over 4 years ago

Clinical • Clinical data • Retrospective data • Journal

EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)

TP53 mutation • KRAS mutation • EGFR mutation • BRAF mutation • PIK3CA mutation • MET amplification • EGFR T790M • EGFR amplification • EGFR C797S • PIK3CA amplification • EGFR mutation + KRAS mutation • EGFR G724S • BRAF mutation + MET amplification • EGFR T790M + KRAS mutation • EGFR mutation + EGFR T790M • EGFR C796S • EGFR C797S + EGFR C796S • EGFR E758D • EGFR G796S • EGFR V802I • EGFR V834L • EGFR mutation + EGFR T790M + EGFR C797S • KRAS mutation + EGFR amplification

Tagrisso (osimertinib)

over4years

[VIRTUAL] Progression after osimertinib in EGFR T790M-mutated non-small cell cancer patients (ERS 2020)

Resistance mechanisms to osimertinib are diverse, therefore re-biopsy and Next Generation Sequencing are important to decide the subsequent strategy.

over 4 years ago

Clinical

EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)

EGFR mutation • PIK3CA mutation • MET amplification • EGFR T790M • ALK fusion • EGFR C797S • PIK3CA amplification • EGFR C797S + EGFR T790M + EGFR exon 19 deletion • EGFR mutation + EGFR T790M • EGFR mutation + EGFR T790M + EGFR C797S • EGFR T790M + exon 19 deletion

Tagrisso (osimertinib)