It has been well established that EGFR Thr790Met is one of the major resistance mechanisms to first- and second-generation EGFR tyrosine kinase inhibitors TKIs. T790M was found in about 50 of EGFR mutant cases that acquired resistance to EGFR TKIs.
Pdf Egfr Tki Resistance In Nsclc Patients Mechanisms And Strategies Semantic Scholar
In non-small-cell lung cancer NSCLC resistance mechanisms to EGFR tyrosine kinase inhibitors TKIs at the level of the individual tumour cell include EGFR TKI-insensitive EGFR-activating.
Egfr tki resistance mechanisms. The left part of the figure represents EGFR-mediated resistance mechanisms whereas the right part depicts EGFR-independent ones. Resistance mechanism against first generation epidermal growth factor receptor tyrosine kinase inhibitor EGFR-TKI. We analyzed mutation concordance across sample types and investigated potential mechanisms that confer primary resistance to EGFR-TKIs in patients with short progression-free survival PFS versus those with long PFS.
Additional mechanisms of EGFR TKI resistance The EGFR -independent resistance mechanisms described above act through the activation of alternative bypass tracks reactivating MAPK and PI3K. For these reasons MET activation is one of the potential mechanisms of resistance to EGFR TKIs in NSCLC. The most common mechanism is the development of acquired EGFR T790M mutation 9.
Other molecular mediators which contribute towards TKI resistance include. Review summarizes the recent findings in mechanisms of resistance to 3rdgeneration EGFRTKIs in advanced NSCLC and provides possible strategies to overcome this resistance. The mechanisms of acquired resistance mainly include an altered EGFR signaling pathway EGFR tertiary mutations.
However it can be rarely found in TKI naïve NSCLC patients. This case report corroborates the in vitro studies suggesting NRAS amplification is a relevant resistance mechanism to EGFR-targeted therapy and should be. Acquired resistance mechanisms to EGFR-TKIs can be broadly grouped into EGFR-dependent or EGFR-independent mechanisms.
Nevertheless whether EGFR Thr790Leu T790L which shares the mutation site of Thr790 with EGFR Thr790Met mediates resistance to EGFR TKIs remains elusive. Osimertinib is a representative of the 3rdgeneration EGFRTKIs that target T790M mutation and has satisfactory efficacy in the treatment of T790Mpositive NSCLC with disease progression following use of 1st or 2ndgeneration EGFRTKIs. Resistance to epidermal growth factor receptor EGFR tyrosine kinase inhibitors TKIs in non small cell lung cancer NSCLC is mediated by two major mechanisms namely secondary mutation T790M in EGFR and cMET amplification.
Mechanisms of Resistance. However the development of acquired resistance to third-generation EGFR-TKI involving the cysteine residue at codon 797 mutation has been observed. B Activation of alternative signaling pathways.
4 EGFR T790M develops in approximately 60 of cases of NSCLC upon treatment with TKIs5 and decreases the affinity of EGFR-TKI binding to the adenosine triphosphate binding pocket of EGFR. In the pale yellow panels are specified clinicaltrialsgov references of. In non-small cell lung cancer NSCLC the activating mutations.
Heterogeneous resistance mechanisms to third-generation EGFR-TKI. In this Review we summarise the scientific literature and evidence on therapy. T790M mutation is the main mechanism of acquired resistance to EGFR TKIs found in up to 60 of post-TKI tumour samples see later.
T790M mutation induces conformational changes on the ATP-binding pocket of EGFRtyrosine kinase domain inhibiting interaction with the drug target site. Osimertiniba third-generation EGFR-TKItargets the T790M mutation and has demonstrated high efficacy against EGFR-mutated lung cancer. Some of the mechanisms are overlapping when osimertinib is administered as a.
A Mutations in the EGFR gene. EGFR-TKI resistance in NSCLC patients. However EGFR T790M mutation is the primary mechanism of 1st and 2ndgeneration EGFRTKI resistance.
The main resistance mechanisms were T790M n 9 MET amplification n 4 and other n 4 Figures 5A S1. Third-generation EGFR-mutant-selective TKIs such as AZD9291 or rociletininb which target Thr790Met-mutant tumours the most common mechanism of EGFR TKI resistance have entered clinical trials and exciting albeit preliminary efficacy data have been reported. Resistance to egfr-tkis is inevitable due to various mechanisms such as the secondary mutation t790m activation of alternative pathways c-met hgf axl aberrance of the downstream pathways k-ras mutations loss of pten impairment of the egfr-tkis-mediated apoptosis pathway bcl2-like 11bim deletion polymorphism histologic.
Other mechanisms of acquired resistance include the activation. A variety of mechanisms of acquired resistance to EGFR TKIs have been reported. Resistance to epidermal growth factor receptor.
Previous studies demonstrated that activation of Hedgehog pathway is a T790M-independent mechanism of EGFR-TKI resistance in EGFR-mutated NSCLC. The most common mechanism of acquired resistance is the development of a second mutation in exon 20 of EGFR known as T790M. As a matter of fact MET amplification is frequently reported as a mechanism of loss of efficacy of EGFR TKI therapy among EGFR mut patients 656667.
All patients had EGFR TKI-sensitizing mutations including EGFR Ex19del L858R G719SC and L861Q. Stars illustrate protein mutations red arrows inhibitory effect and green arrows activating effects. The epidermal growth factor receptor EGFR is a kind of receptor tyrosine kinase RTK that plays a critical role in the initiation and development of malignant tumors via modulating downstream signaling pathways.
Several mechanisms of resistance have been described to egfr-tkis such as the occurrence of secondary mutation t790m c797s the activation of alternative signalling met hgf axl hh igf-1r the aberrance of the downstream pathways akt mutations loss of pten the impairment of the egfr-tkis-mediated apoptosis pathway bcl2-like 11bim.
Mechanisms Of Acquired Resistance To First And Second Generation Egfr Tyrosine Kinase Inhibitors Annals Of Oncology
Main Mechanisms Of Acquired Resistance To Epidermal Growth Factor Download Scientific Diagram
Figure 1 Mechanisms Of Resistance To Egfr Tkis And Development Of A New Generation Of Drugs In Non Small Cell Lung Cancer