BACKGROUND/AIM: We investigated efficacy differences for afatinib versus gefitinib in non-small-cell lung cancer (NSCLC) according to epidermal growth factor receptor (EGFR) mutations. PATIENTS AND METHODS: We retrospectively analysed data for 343 patients with NSCLC with performance status 1 having EGFR mutations treated with gefitinib or afatinib. Overall response rate (ORR) was tested by Fisher's exact test. Overall (OS) and progression-free (PFS) survival were estimated by Kaplan-Meier method. RESULTS: ORR did not differ in any group or subgroup. Among all patients, we observed significantly longer PFS for those treated with afatinib vs. gefitinib (median 13.4 vs. 9.5 months, p=0.026), but only a nonsignificant trend was observed for OS. We showed nonsignificant trends of better PFS and OS using afatinib for exon 19 deletion and L858R subgroups. We observed no significant PFS differences for other EGFR mutations but a nonsignificant trend towards better OS for those treated with afatinib. CONCLUSION: Afatinib led to longer PFS for patients with common EGFR mutations but not for those with rare mutations.

• Klíčová slova
• Afatinib, NSCLC, gefitinib, real world data,
• MeSH
• afatinib terapeutické užití   MeSH
• dospělí MeSH
• erbB receptory genetika   MeSH
• gefitinib terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mutace MeSH
• nádory plic farmakoterapie   genetika   mortalita   patologie   MeSH
• nemalobuněčný karcinom plic farmakoterapie   genetika   mortalita   patologie   MeSH
• progrese nemoci MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• afatinib MeSH
• EGFR protein, human MeSH Prohlížeč
• erbB receptory MeSH
• gefitinib MeSH

BACKGROUND: Malignant tumours of the trachea, the lungs, and the bronchus are the second most common type of tumour in the Czech Republic. Approximately three-quarters of cases are dia-gnosed in an advanced stage (IIIB-IV) and are one of the most common causes of death in all cancer groups. Targeted therapy brings a certain level of the improvement of prognostic outlook. In the Czech Republic, 1st and 2nd generation of tyrosine kinase inhibitors (gefitinib, erlotinib, afatinib) are indicated in the first-line anticancer treatment in non-small-cell lung cancer in locally advanced and metastatic stage, with proved activating mutation status of the epidermal growth factor receptor. Erlotinib is also indicated for use in the second or third line of anticancer treatment after a documented failure of previous chemotherapy. CASE: A 70-year-old patient with lung adenocarcinoma, sensitive mutation in exon 19 of epidermal growth factor receptor gene, clinical-stage IV (according to the 7th edition of TNM classification), demonstrating long-term stable disease on erlotinib treatment after first-line gefitinib failure and second-line carboplatin-bevacizumab-paclitaxel combination chemotherapy failure. The disease treated with erlotinib has been stable for 48 months, although the dose has been reduced to 100mg per day due to side effects (rash). CONCLUSION: While the efficacy of a gefitinib treatment in this case report was comparable to clinical trials results, the progression interval in this particular patient when treated with erlotinib is about 5 times longer compared to the progression observed in clinical trials. Another interesting fact is also a significant difference in the effect of these two tyrosine kinase inhibitors, which have shown comparable efficacy in clinical trials.

• Klíčová slova
• adenocarcinoma of lung, erlotinib, gefitinib, targeted therapy, tyrosine kinase inhibitors,
• MeSH
• adenokarcinom plic farmakoterapie   genetika   MeSH
• bevacizumab terapeutické užití   MeSH
• erbB receptory genetika   MeSH
• erlotinib terapeutické užití   MeSH
• gefitinib terapeutické užití   MeSH
• karboplatina terapeutické užití   MeSH
• lidé MeSH
• mutace MeSH
• nádory plic farmakoterapie   genetika   MeSH
• paclitaxel terapeutické užití   MeSH
• protinádorové látky terapeutické užití   MeSH
• senioři MeSH
• záchranná terapie metody   MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• bevacizumab MeSH
• EGFR protein, human MeSH Prohlížeč
• erbB receptory MeSH
• erlotinib MeSH
• gefitinib MeSH
• karboplatina MeSH
• paclitaxel MeSH
• protinádorové látky MeSH

Lysosomal sequestration of anticancer therapeutics lowers their cytotoxic potential, reduces drug availability at target sites, and contributes to cancer resistance. Only recently has it been shown that lysosomal sequestration of weak base drugs induces lysosomal biogenesis mediated by activation of transcription factor EB (TFEB) which, in turn, enhances their accumulation capacity, thereby increasing resistance to these drugs. Here, we addressed the question of whether lysosomal biogenesis is the only mechanism that increases lysosomal sequestration capacity. We found that lysosomal sequestration of some tyrosine kinase inhibitors (TKIs), gefitinib (GF) and imatinib (IM), induced expansion of the lysosomal compartment. However, an expression analysis of lysosomal genes, including lysosome-associated membrane proteins 1, 2 (LAMP1, LAMP2), vacuolar ATPase subunit B2 (ATP6V1B2), acid phosphatase (ACP), and galactosidase beta (GLB) controlled by TFEB, did not reveal increased expression. Instead, we found that both studied TKIs, GF and IM, induced lysosomal fusion which was dependent on nicotinic acid adenine dinucleotide phosphate (NAADP) mediated Ca2+signaling. A theoretical analysis revealed that lysosomal fusion is sufficient to explain the enlargement of lysosomal sequestration capacity. In conclusion, we demonstrated that extracellular TKIs, GF and IM, induced NAADP/Ca2+ mediated lysosomal fusion, leading to enlargement of the lysosomal compartment with significantly increased sequestration capacity for these drugs without apparent lysosomal biogenesis.

• Klíčová slova
• Hl-60 cells, K562 cells, lysosomal fusion, lysosomal sequestration capacity, tyrosine kinase inhibitors,
• MeSH
• biogeneze organel MeSH
• buňky K562 MeSH
• chemorezistence účinky léků   MeSH
• gefitinib farmakologie   MeSH
• imatinib mesylát farmakologie   MeSH
• lidé MeSH
• lyzozomy účinky léků   metabolismus   MeSH
• nádorové buněčné linie MeSH
• protinádorové látky farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• transkripční faktory BHLH-Zip účinky léků   metabolismus   MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• gefitinib MeSH
• imatinib mesylát MeSH
• protinádorové látky MeSH
• TFEB protein, human MeSH Prohlížeč
• transkripční faktory BHLH-Zip MeSH
• tyrosinkinasy MeSH

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) represent novel effective agents approved for the treatment of patients with advanced-stage NSCLC. KRAS mutations have been reported as a negative prognostic and predictive factor in patients with NSCLC treated with EGFR-TKIs. Several studies have recently shown that statins can block tumour cell growth, invasion and metastatic potential. We analysed clinical data of 67 patients with locally advanced (IIIB) or metastatic stage (IV) NSCLC harbouring Kirsten rat sarcoma viral oncogene (KRAS) mutation treated with erlotinib or gefitinib. Twelve patients were treated with combination of EGFR-TKI and statin and 55 patients were treated with EGFR-TKI alone. Comparison of patients' survival (progression-free survival (PFS) and overall survival (OS)) according to the treatment used was performed using the Gehan-Wilcoxon test. The median of PFS and OS for patients treated with EGFR-TKI alone was 1.0 and 5.4 months compared to 2.0 and 14.0 months for patients treated with combination of EGFR-TKI and statin (p = 0.025, p = 0.130). In conclusion, the study results suggest significant improvement of PFS for patients treated with combination of statin and EGFR-TKI, and the difference in OS was not significant.

• MeSH
• adenokarcinom farmakoterapie   genetika   patologie   MeSH
• chinazoliny aplikace a dávkování   MeSH
• erbB receptory antagonisté a inhibitory   genetika   MeSH
• erlotinib MeSH
• gefitinib MeSH
• inhibitory proteinkinas aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• nemalobuněčný karcinom plic farmakoterapie   genetika   patologie   MeSH
• přežití bez známek nemoci MeSH
• prognóza MeSH
• protoonkogenní proteiny p21(ras) MeSH
• protoonkogenní proteiny genetika   MeSH
• Ras proteiny genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• statiny aplikace a dávkování   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chinazoliny MeSH
• EGFR protein, human MeSH Prohlížeč
• erbB receptory MeSH
• erlotinib MeSH
• gefitinib MeSH
• inhibitory proteinkinas MeSH
• KRAS protein, human MeSH Prohlížeč
• protoonkogenní proteiny p21(ras) MeSH
• protoonkogenní proteiny MeSH
• Ras proteiny MeSH
• statiny MeSH

Nowadays, EGFR TKIs (epidermal growth factor receptor-tyrosine kinase inhibitors) targeted therapy is well established treatment for patients with the so-called EGFR common mutations with advanced or metastatic nonsmall cell lung cancer. The efficacy for the so-called rare and especially for the very rare complex EGFR mutations is not clear. We describe a case of a 63- year-old female with metastatic nonsmall cell lung cancer with complex EGFR mutation (G719X + S768I) who had been treated by gefitinib. She achieved progression free survival within eight months. Then, we discuss our case with other literature case reports. Together, it seems that described complex EGFR mutation has a relatively good sensitivity for EGFR TKIs treatment.Key words: nonsmall cell lung cancer - EGFR gene - EGFR protein - complex mutations - rare EGFR mutations - EGFR TKIs.

• MeSH
• adenokarcinom plic MeSH
• adenokarcinom diagnostické zobrazování   farmakoterapie   genetika   sekundární   MeSH
• chinazoliny terapeutické užití   MeSH
• erbB receptory genetika   MeSH
• gefitinib MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory plic diagnostické zobrazování   farmakoterapie   genetika   sekundární   MeSH
• nemalobuněčný karcinom plic diagnostické zobrazování   farmakoterapie   genetika   patologie   MeSH
• radiografie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• chinazoliny MeSH
• erbB receptory MeSH
• gefitinib MeSH
• inhibitory proteinkinas MeSH

Inappropriate activation of epidermal growth factor receptor (EGFR) plays a causal role in many cancers including colon cancer. The activation of EGFR by phosphorylation is balanced by receptor kinase and protein tyrosine phosphatase activities. However, the mechanisms of negative EGFR regulation by tyrosine phosphatases remain largely unexplored. Our previous results indicate that protein tyrosine phosphatase receptor type O (PTPRO) is down-regulated in a subset of colorectal cancer (CRC) patients with a poor prognosis. Here we identified PTPRO as a phosphatase that negatively regulates SRC by directly dephosphorylating Y416 phosphorylation site. SRC activation triggered by PTPRO down-regulation induces phosphorylation of both EGFR at Y845 and the c-CBL ubiquitin ligase at Y731. Increased EGFR phosphorylation at Y845 promotes its receptor activity, whereas enhanced phosphorylation of c-CBL triggers its degradation promoting EGFR stability. Importantly, hyperactivation of SRC/EGFR signaling triggered by loss of PTPRO leads to high resistance of colon cancer to EGFR inhibitors. Our results not only highlight the PTPRO contribution in negative regulation of SRC/EGFR signaling but also suggest that tumors with low PTPRO expression may be therapeutically targetable by anti-SRC therapies.

• MeSH
• buňky HT-29 MeSH
• Caco-2 buňky MeSH
• chinazoliny farmakologie   MeSH
• epidermální růstový faktor farmakologie   MeSH
• erbB receptory antagonisté a inhibitory   metabolismus   MeSH
• fosforylace MeSH
• gefitinib MeSH
• HCT116 buňky MeSH
• HEK293 buňky MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• MAP kinasový signální systém MeSH
• messenger RNA genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory tračníku farmakoterapie   enzymologie   genetika   patologie   MeSH
• protoonkogenní proteiny c-cbl metabolismus   MeSH
• signální transdukce MeSH
• skupina kinas odvozených od src-genu metabolismus   MeSH
• tyrosinfosfatasy receptorového typu, třída 3 biosyntéza   genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CBL protein, human MeSH Prohlížeč
• chinazoliny MeSH
• EGFR protein, human MeSH Prohlížeč
• epidermální růstový faktor MeSH
• erbB receptory MeSH
• gefitinib MeSH
• inhibitory proteinkinas MeSH
• messenger RNA MeSH
• protoonkogenní proteiny c-cbl MeSH
• PTPRO protein, human MeSH Prohlížeč
• skupina kinas odvozených od src-genu MeSH
• tyrosinfosfatasy receptorového typu, třída 3 MeSH

• MeSH
• bevacizumab MeSH
• chinazoliny terapeutické užití   MeSH
• erlotinib MeSH
• gefitinib MeSH
• glutamáty terapeutické užití   MeSH
• guanin analogy a deriváty   terapeutické užití   MeSH
• humanizované monoklonální protilátky terapeutické užití   MeSH
• lidé MeSH
• nádory plic farmakoterapie   MeSH
• nemalobuněčný karcinom plic farmakoterapie   MeSH
• pemetrexed MeSH
• protinádorové látky terapeutické užití   MeSH
• registrace * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• bevacizumab MeSH
• chinazoliny MeSH
• erlotinib MeSH
• gefitinib MeSH
• glutamáty MeSH
• guanin MeSH
• humanizované monoklonální protilátky MeSH
• pemetrexed MeSH
• protinádorové látky MeSH

BACKGROUND: Molecular targeted therapy based on tyrosine kinase inhibitors, directed at the epidermal growth factor receptor (EGFR) is one of novel options for management of NSCLC. EGFR gene mutations, exon 19 deletions and exon 21 point mutations (L858R) are good predictors of response to EGFR-TKI treatment. The aim of this study was to assess the incidence of EGFR mutations in a large cohort of Europeans with advanced NSCLC and subsequently to evaluate their impact on the effect of EGFR-TKI treatment. PATIENTS AND METHODS: In total, 613 patients with advanced stage NSCLC (IIIB, IV) were genetically tested. The effect of treatment was evaluated in 410 patients treated with EGFR-TKI. Survival was evaluated using Kaplan-Meier method, and statistical comparison was performed using log-rank test. RESULTS: EGFR mutations were detected in 73 (11.9%) patients. Exon 19 deletions were detected in 49 patients, exon 21 point mutations (L858R) were detected in 22 patients, and both mutation types were detected in 2 patients. An increased incidence of EGFR mutations among patients with adenocarcinoma (14.9% vs 7.8%, p = 0.008), women (20.2% vs 7.1%, p < 0.001) and nonsmokers (29.9% vs 7.0%, p < 0.001) was demonstrated. Sixty patients with EGFR mutation and 350 patients with wild-type EGFR were treated with EGFR-TKI. Median PFS in patients harboring EGFR mutation was 7.2 vs 2.0 months in patients harboring wild-type EGFR (p < 0.001), median OS in patients harboring EGFR mutation was 14.5 vs 7.5 months in patients harboring wild-type EGFR (p = 0.019). CONCLUSION: The incidence of EGFR mutations in the studied population, their increased incidence among patients with adenocarcinoma, women and non-smokers correlated with data previously published. Results of survival analysis in patients treated with EGFR-TKI confirmed high potential of EGFR mutations to predict good effect of the EGFR-TKI treatment. Genetic testing in patients with NSCLC should be a standard part of diagnostic procedures

• MeSH
• chinazoliny terapeutické užití   MeSH
• erbB receptory genetika   MeSH
• erlotinib MeSH
• gefitinib MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• mutace * MeSH
• nádory plic farmakoterapie   genetika   mortalita   MeSH
• nemalobuněčný karcinom plic farmakoterapie   genetika   mortalita   MeSH
• protinádorové látky terapeutické užití   MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chinazoliny MeSH
• erbB receptory MeSH
• erlotinib MeSH
• gefitinib MeSH
• inhibitory proteinkinas MeSH
• protinádorové látky MeSH
• tyrosinkinasy MeSH

PURPOSE: We investigated whether the pharmacokinetics and tolerability of gefitinib were altered in patients with hepatic impairment due to cirrhosis or hepatic metastases in two open, parallel-group, multicenter studies. METHODS: In Study 1, subjects with normal hepatic function or mild, moderate, or severe hepatic impairment (Child-Pugh criteria) due to cirrhosis received single-dose gefitinib 250 mg (n = 10 per group). In Study 2, patients with solid malignant tumors with normal liver biochemistry (n = 18), moderate (n = 16), or severe (n = 7) hepatic impairment (liver biochemistry tests) due to metastases received gefitinib 250 mg daily for 28 days. RESULTS: In Study 1, the geometric mean area under the plasma concentration-time curve (AUC) for gefitinib was significantly higher in patients with hepatic impairment compared with healthy subjects; hepatic impairment was associated with reduced gefitinib plasma clearance, longer half-life, and reduced plasma metabolite levels. In Study 2, the geometric mean gefitinib steady-state AUC during the 24-h dosing interval was slightly, but not significantly, higher in patients with moderate hepatic impairment; there were, however, no significant differences between groups in gefitinib and metabolite pharmacokinetic parameters. In both studies, gefitinib was well tolerated across all cohorts. CONCLUSIONS: We conclude that the effect of hepatic impairment on gefitinib pharmacokinetics depends on the underlying etiology of that impairment and its classification.

• MeSH
• chinazoliny škodlivé účinky   farmakokinetika   MeSH
• dospělí MeSH
• gefitinib MeSH
• lidé středního věku MeSH
• lidé MeSH
• nemoci jater etiologie   metabolismus   MeSH
• plocha pod křivkou MeSH
• protinádorové látky farmakokinetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chinazoliny MeSH
• gefitinib MeSH
• protinádorové látky MeSH

Even though lung cancer incidence began to decline in the majority of industrialized countries, is still belong to cancers with one of the highest incidence and mortality rates. In the Czech Republic, epidermal growth factor receptor (EGFR) kinase activity inhibitors erlotinib and gefitinib are approved for the use as the second- and third-line treatment of non-small-cell lung cancer. In a cohort of non-small-cell lung cancer patients, erlotinib administration led to tumour regression in less than 20% of patients. However, when used in patients with EGFR-activating mutations, e.g. L858R or delE746-A750, the response rate increased to 75-82% in several parallel clinical studies. Similarly, improved response rate was reported in patients bearing amplified wild-type EGFR gene. In contrary, patients with T790M, D761Y, L747S, and T854A mutations (and some other rare abberations) were found to be resistant to treatment with small-molecule inhibitors targeting the active site of the kinase domain. These mutations do not change the EGFR affinity to gefitinib or erlotinib but the mutated receptor is able to bind ATP into its active site even in the presence of erlotinib or gefitinib, similar to a wild-type receptor without an inhibitor. Besides that, when the EGFR molecule bears both the activating (e.g. L858R) and resistance-inducing mutation (e.g. T790M), the tumour acquires resistance to both erlotinib and gefitinib treatment. Currently, research focuses on a development of new strategies that would allow treatment of patients bearing mutations inducing resistance to the small-molecule inhibitors targeted on the active site of EGFR kinase domain. Contrary to the current guidelines for Czech oncologists, identification of EGFR with any of the above mentioned resistance-inducing somatic mutations should be considered as an explicit contraindication for non-small-cell cancer treatment using small-molecule EGFR kinase activity inhibitors erlotinib or gefitinib. This should also include patients in whom a resistance-inducing mutation is detected together with any of the activating mutations or deletions.

• MeSH
• chemorezistence genetika   MeSH
• chinazoliny terapeutické užití   MeSH
• erbB receptory antagonisté a inhibitory   genetika   MeSH
• erlotinib MeSH
• gefitinib MeSH
• lidé MeSH
• mutace MeSH
• nádory plic farmakoterapie   genetika   MeSH
• nemalobuněčný karcinom plic farmakoterapie   genetika   MeSH
• protinádorové látky terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• chinazoliny MeSH
• erbB receptory MeSH
• erlotinib MeSH
• gefitinib MeSH
• protinádorové látky MeSH