Since the 2004 discovery gene activating mutations of the epidermal growth factor receptor (EGFR) and EGFR tyrosine kinase inhibitor (TKI) the efficacy of the treatment of non-small cell lung cancer (NSCLC), the number of prospective clinical studies have confirmed, EGFR activating mutation positive NSCLC patients with EGFR-TKI response rate was significantly higher than that of wild-type EGFR NSCLC patients, progression-free survival (PFS) and overall survival (OS) significantly longer period. Nevertheless, the majority of patients with EGFR mutation positive PFS no more than 12 to 14 months of TKI resistant. Acquired resistance mechanisms and their clinical coping strategies become another hotspot in the field of targeted therapy.
Resistance mechanisms
Mechanisms: resistance mutations
The T790M mutation is a point mutation in the EGFR 20 exons, is one of the more recognized resistance mechanisms.
T790M cause TKI resistance mechanism is not fully understood. The initial studies, T790M, may change the crystal structure of the binding pocket of the kinase domain of adenosine triphosphate (ATP), the closure the combination of TKI kinase domain. The latest research shows that the L858R to merger T790M mutation of the ATP affinity than mere L858R, TKI ATP competitive kinase inhibitors, it led to the TKI kinase domain binding rate decreases.
One of the T790M controversy is the mutations are generated in the TKI therapy or originally existed TKI therapy alternatives were found. Initially, the T790M only in TKI treatment failure in patients with NSCLC specimens were found, but then without any treatment specimens were found, so that the mutation is present in the tumor without TKI therapy, but only seen in a small number of cell clones, selected in the treatment was due to the resistance of these cell clones on the TKI.
The similar T790M resistance mutation D761Y, L747S and T854A, etc., these mutations are collectively referred to as "non-T790M secondary mutation", less than 5% of the total incidence.
Mechanism 2: bypass activation pathway
MET amplification is found in 2007, another EGFR-TKI acquired resistance mechanisms.
MET is a transmembrane tyrosine kinase receptor. Acquired resistance to TKI EGFR mutation-positive NSCLC patients, about 20% of the wild-type MET gene amplification, and most of MET amplification before treatment. MET and ErbB family members, bypassing EGFR activation downstream of AKT-mediated signaling pathways to promote tumor cell growth and inhibited apoptosis. RNA interference in vitro experiments, the MET signaling pathway, recoverability resistance of gefitinib sensitivity. Inhibition of EGFR and MET, and MET amplification mediated TKI resistance can be overcome.
Some receptor similar to the MET role. Recent in vitro TKI resistant model, insulin-like growth factor 1 receptor (IGF-
1R) also can be bypassed EGFR, activation of its downstream signaling pathways, but due to technical reasons, it is difficult to IGF-1R activation detection in patient specimens. These bypass mechanisms of resistance of EGFR, activation of downstream signaling pathways are collectively referred to as the "bypass activation pathway.
TKI resistant EGFR mutation-positive patients, about 30% to 40% neither secondary mutations and MET amplification also exploring the mechanisms of resistance in these patients.
Clinical strategies
Strategy 1: Continue with EGFR-TKI
TKI therapy resistant EGFR mutation-positive NSCLC patients continue to use gefitinib or erlotinib, gefitinib, erlotinib seems to have some clinical benefit. Yokouchi (Yokouchi) and Rielly (Riely) reported two studies show progress again gefitinib or erlotinib, gefitinib, erlotinib may slow down the speed of clinical deterioration, stable part of the progress of the lesion, but the majority of patients continue to progress .
Another frequently discussed issues is replaced with erlotinib after gefitinib treatment progress, is valid. This vision is rooted in the gefitinib clinical dose of 250 mg / d, below the maximum tolerated dose (1000 mg / d), plasma steady-state concentration of no more than 0.5 μmol / L; while erlotinib Nepal clinical dose (150 mg / d) is the maximum tolerated dose, plasma steady-state concentration of more than 1.5 μmol / L. The pre-clinical in vitro studies have shown that more than 5 μmol / L erlotinib concentration required to inhibit EGFR mutation-positive NSCLC cell lines containing the T790M mutation or MET amplification gefitinib or erlotinib. Gefitinib Nepal resistant EGFR mutation positive tumors, mostly associated with the T790M mutation or MET amplification, that this tumor erlotinib cross-resistance.
Korea two Phase Ⅱ clinical studies have shown that the anti-tumor activity of erlotinib (150 mg / d), for the by gefitinib Nepal original, or patients with acquired resistance to erlotinib is very limited, more than 80% of patients with the disease quickly progress. However, due to appear L747S mutation on non imatinib-resistant, erlotinib effectively.
In short, TKI after progression to continue using the TKI seems to have some benefit, but the benefit is very limited.
Strategy 2: development of novel EGFR-TKI
Pre-clinical studies have shown, EGFR irreversible inhibitors can inhibit the in vitro T790M, Since then, many the EGFR irreversible inhibitor was developed, called "second-generation EGFR-TKI from pre-clinical studies gradually toward clinical research more neratinib, XL647, BIBW 2992 and PF-00,299,804.
Neratinib pan-ErbB (EGFR, ErbB2 and ErbB3) irreversible TKI. Results based on the Phase I study, ongoing clinical studies, to explore in NSCLC patients with gefitinib or erlotinib, gefitinib, erlotinib after treatment progress, neratinib (240 mg / d) whether it can overcome the T790M mutation or MET amplification cause TKI resistance. But some pre-clinical studies show adverse results, an EGFR 19 exon deletion cell lines exposed to neratinib PC-9, the T790M mutation; L858R-T790M tumors in mouse models, tumor alone neratinib remission. Therefore neratinib whether the T790M mutation is not yet known.
XL647 irreversible inhibition of EGFR, human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor 2 (VEGFR-2) and EphB4, L858R-T790M mutation model can inhibit tumor growth.
In 2008, a Phase II clinical study of XL647 preliminary show 34 cases of NSCLC patients with gefitinib or erlotinib, gefitinib, erlotinib remission for more than 3 months after the occurrence of disease progression or associated with the T790M mutation, with XL647 ( 300 mg / d) after treatment, only partial remission, the patients not to smoke, missing exon 19 T790M mutation in plasma; T790M mutation-positive patients without remission, most of the progress in the two months.
BIBW 2992 is an irreversible TKI of EGFR and ErbB2. In a Phase II clinical study, BIBW 2992 in exon 19 deletion the L858R, the L861Q and the G719S/S768I, mutations in patients eased. A BIBW 2992 third-line treatment failure of chemotherapy benefit erlotinib gefitinib or erlotinib, gefitinib in NSCLC progress in clinical research is being carried out. BIBW 2992 compared to placebo, and third-line treatment of gefitinib or erlotinib, gefitinib, erlotinib treatment failure NSCLC randomized II b / III clinical studies are being conducted. These studies will help determine whether BIBW 2992 can benefit to gefitinib or erlotinib, gefitinib, erlotinib resistant patients.
PF-00299804 is a pan-ErbB TKI inhibitors. Phase I clinical study in patients with T790M mutation positive disease remission. PF-00299804 (45 mg / d) treatment of KRAS wild-type, chemotherapy and erlotinib treatment failure NSCLC patients II clinical study being undertaken.
Strategy 3: treatment for other targets
Emerging targeted drugs for these bypass the bypass activation pathway play an important role in the EGFR-TKI resistant.
MET-TKI may play a role in patients accompanied MET amplification. The pre-clinical studies have shown that EGFR-TKI MET-TKI combined with EGFR mutation positive and accompanied by MET amplification cell lines, but both used alone are ineffective. An important issue is, about half having the MET amplification of the patient while having the T790M mutation, so MET-TKI may need with the T790M inhibitors joint.
XL184 is a novel TKI, of MET, VEGFR-2 inhibition and RET.
The the other MET inhibitor, such as ARQ197, PF-2,341,066, SGX523 also conducting clinical research.
PF-2341066 is a selective c-MET and ALK receptor tyrosine kinase inhibitor, in Phase I clinical studies show better tumor control, especially for ALK-EML4 fusion gene-positive patients. PF-2341066 II / III clinical study being carried out, it has become a new hot spot in the field of targeted therapy.
For other possible bypass activation pathway, some drugs, such as IGF-1R inhibitors, heat shock protein 90 inhibitors and other related research is also underway.
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