Olmutinib Reverses Thioacetamide-Induced Cell Cycle Gene Alterations in Mice Liver and Kidney Tissues, While Wheat Germ Treatment Exhibits Limited Efficacy at Gene Level.

Background and Objectives: TAA is potent hepatic/renal toxicant. Conversely, WGO is a potent dietary supplement with impressive antioxidant properties. Olmutinib is an apoptotic chemotherapy drug that does not harm the liver or kidney. This study investigated the impact of olmutinib and wheat germ oil (WGO) on Thioacetamide (TAA)-induced gene alterations in mice liver and kidney tissues. Materials and Methods: Adult male C57BL/6 mice were exposed to 0.3% TAA in drinking water for 14 days, followed by the oral administration of olmutinib (30 mg/kg) and WGO (1400 mg/kg) for 5 consecutive days. Treatment groups included the following: groups I (control), II (TAA-exposed), III (TAA + olmutinib), IV (TAA + WGO), and V (TAA + olmutinib + WGO). Results: The findings revealed that TAA exposure increased MKi67 and CDKN3 gene expression in liver and kidney tissues. Olmutinib treatment effectively reversed these TAA-induced effects, significantly restoring MKi67 and CDKN3 gene expression. WGO also reversed MKi67 effects in the liver but exhibited limited efficacy in reversing CDKN3 gene alterations induced by TAA exposures in both the liver and kidney. TAA exposure showed the tissue-specific expression of TP53, with decreased expression in the liver and increased expression in the kidney. Olmutinib effectively reversed these tissue-specific alterations in TP53 expression. While WGO treatment alone could not reverse the gene alterations induced by TAA exposure, the co-administration of olmutinib and WGO exhibited a remarkable potentiation of therapeutic effects in both the liver and kidney. The gene interaction analysis revealed 77.4% of physical interactions and co-localization between MKi67, CDKN3, and TP53 expressions. Protein-protein interaction networks also demonstrated physical interactions between MKi67, TP53, and CDKN3, forming complexes or signaling cascades. Conclusions: It was predicted that the increased expression of the MKi67 gene by TAA leads to the increase in TP53, which negatively regulates the cell cycle via increased CDKN3 expression in kidneys and the restoration of TP53 levels in the liver. These findings contribute to our understanding of the effects of olmutinib and WGO on TAA-induced gene expression changes and highlight their contrasting effects based on cell cycle alterations.

In Silico and In Vitro Exploration of Poziotinib and Olmutinib Synergy in Lung Cancer: Role of hsa-miR-7-5p in Regulating Apoptotic Pathway Marker Genes.

Background and objectives: Non-small cell lung cancer (NSCLC) is often caused by EGFR mutations, leading to overactive cell growth pathways. Drug resistance is a significant challenge in lung cancer treatment, affecting therapy effectiveness and patient survival. However, combining drugs in research shows promise in addressing or delaying resistance, offering a more effective approach to cancer treatment. In this study, we investigated the potential alterations in the apoptotic pathway in A549 cells induced by a combined targeted therapy using tyrosine kinase inhibitors (TKIs) olmutinib and poziotinib, focusing on cell proliferation, differential gene expression, and in silico analysis of apoptotic markers. Methods: A combined targeted therapy involving olmutinib and poziotinib was investigated for its impact on the apoptotic pathway in A549 cells. Cell proliferation, quantitative differential gene expression, and in silico analysis of apoptotic markers were examined. A549 cells were treated with varying concentrations (1, 2.5, and 5 µM) of poziotinib, olmutinib, and their combination. Results: Treatment with poziotinib, olmutinib, and their combination significantly reduced cell proliferation, with the most pronounced effect at 2.5 µM (p < 0.005). A synergistic antiproliferative effect was observed with the combination of poziotinib and olmutinib (p < 0.0005). Quantitative differential gene expression showed synergistic action of the drug combination, impacting key apoptotic genes including STK-11, Bcl-2, Bax, and the Bax/Bcl-2 ratio. In silico analysis revealed direct interactions between EGFR and ERBB2 genes, accounting for 77.64% of their interactions, and 8% co-expression with downstream apoptotic genes. Molecular docking indicated strong binding of poziotinib and olmutinib to extrinsic and intrinsic apoptotic pathway markers, with binding energies of -9.4 kcal/mol and -8.5 kcal/mol, respectively, on interacting with STK-11. Conclusions: Combining poziotinib and olmutinib therapies may significantly improve drug tolerance and conquer drug resistance more effectively than using them individually in lung cancer patients, as suggested by this study's mechanisms.

Olmutinib in T790M-positive non-small cell lung cancer after failure of first-line epidermal growth factor receptor-tyrosine kinase inhibitor therapy: A global, phase 2 study.

BACKGROUND: In this open-label, international phase 2 study, the authors assessed the efficacy and safety of olmutinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had a confirmed T790M mutation and disease progression on previous epidermal growth factor receptor-tyrosine kinase inhibitor therapy. METHODS: Patients aged ≥20 years received once-daily oral olmutinib 800 mg continuously in 21-day cycles. The primary endpoint was the objective response rate (patients who had a confirmed best overall response of a complete or partial response), assessed by central review. Secondary endpoints included the disease control rate, the duration of objective response, progression-free survival, and overall survival. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). RESULTS: Overall, 162 patients (median age, 63 years; women, >60%) were enrolled from 68 sites in 9 countries. At the time of database cutoff, 23.5% of enrolled patients remained on treatment. The median treatment duration was 6.5 months (range, 0.03-21.68 months). Overall, 46.3% of patients (95% CI, 38.4%-54.3%) had a confirmed objective response (all partial responses). The best overall response (the objective response rate regardless of confirmation) was 51.9% (84 patients; 95% CI, 43.9%-59.8%). The confirmed disease control rate for all patients was 86.4% (95% CI, 80.2%-91.3%). The median duration of objective response was 12.7 months (95% CI, 8.3-15.4 months). Estimated median progression-free survival was 9.4 months (95% CI, 6.9-12.3 months), and estimated median overall survival was 19.7 months (95% CI, 15.1 months to not reached). All patients experienced treatment-emergent adverse events, and 71.6% of patients had grade ≥3 treatment-emergent adverse events. CONCLUSIONS: Olmutinib has meaningful clinical activity and a manageable safety profile in patients with T790M-positive non-small cell lung cancer who received previous epidermal growth factor receptor-tyrosine kinase inhibitor therapy.

Design, Synthesis, and Antitumor Activity of Olmutinib Derivatives Containing Acrylamide Moiety.

Two series of olmutinib derivatives containing an acrylamide moiety were designed and synthesized, and their IC50 values against cancer cell lines (A549, H1975, NCI-H460, LO2, and MCF-7) were evaluated. Most of the compounds exhibited moderate cytotoxic activity against the five cancer cell lines. The most promising compound, H10, showed not only excellent activity against EGFR kinase but also positive biological activity against PI3K kinase. The structure-activity relationship (SAR) suggested that the introduction of dimethylamine scaffolds with smaller spatial structures was more favorable for antitumor activity. Additionally, the substitution of different acrylamide side chains had different effects on the activity of compounds. Generally, compounds H7 and H10 were confirmed as promising antitumor agents.

Icotinib, Almonertinib, and Olmutinib: A 2D Similarity/Docking-Based Study to Predict the Potential Binding Modes and Interactions into EGFR.

In the current study, a 2D similarity/docking-based study was used to predict the potential binding modes of icotinib, almonertinib, and olmutinib into EGFR. The similarity search of icotinib, almonertinib, and olmutinib against a database of 154 EGFR ligands revealed the highest similarity scores with erlotinib (0.9333), osimertinib (0.9487), and WZ4003 (0.8421), respectively. In addition, the results of the docking study of the three drugs into EGFR revealed high binding free energies (ΔGb = -6.32 to -8.42 kcal/mol) compared to the co-crystallized ligands (ΔGb = -7.03 to -8.07 kcal/mol). Analysis of the top-scoring poses of the three drugs was done to identify their potential binding modes. The distances between Cys797 in EGFR and the Michael acceptor sites in almonertinib and olmutinib were determined. In conclusion, the results could provide insights into the potential binding characteristics of the three drugs into EGFR which could help in the design of new more potent analogs.

Detection and characterization of olmutinib reactive metabolites by LC-MS/MS: Elucidation of bioactivation pathways.

Olmutinib (Olita™) is an orally bioavailable third generation epidermal growth factor receptor tyrosine kinase inhibitor. Olmutinib was approved in South Korea in May 2016 for the treatment of patients suffering from locally advanced or metastatic epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer. Reactive olmutinib intermediates may be responsible for the severe side effects associated with the treatment. However, literature review revealed no previous reports on the structural identification of reactive olmutinib metabolites. In this work, the formation of reactive olmutinib metabolites in rat liver microsomes was investigated. Methoxylamine, glutathione, and potassium cyanide were used as capturing agents for aldehyde, iminoquinones, and iminium intermediates, respectively. The stable complexes formed were identified using liquid chromatography-tandem mass spectrometry. The major phase I metabolic pathway observed in vitro was hydroxylation of the piperazine ring. Seven potential reactive intermediates were characterized, including three iminium ions, three iminoquinones, and one aldehyde. Based on the findings, various bioactivation pathways were postulated. Hence, identifying the reactive intermediates of olmutinib that may be the cause of severe side effects can provide new insights, leading to improved treatments for patients.

Targeting EGFR T790M mutation in NSCLC: From biology to evaluation and treatment.

The identification of EGFR mutations and their respectively tyrosine kinase inhibitors (TKIs), changed dramatically treatment and survival of patients with EGFR-positive lung cancer. Nowadays, different EGFR TKIs as afatinib, erlotinib and gefitinib are approved worldwide for the treatment of NSCLC harbouring EGFR mutations, in particular exon 19 deletions or exon 21 (Leu858Arg) substitution EGFR mutations. In first-line setting, when comparing with platinum-based chemotherapy, these target drugs improves progression-free survival, response rate and quality of life. Unfortunately, the development of different mechanism of resistance, limits the long term efficacy of these agents. The most clear mechanism of resistance is the development of EGFR Thr790Met mutation. Against this new target, different third-generation EGFR-mutant-selective TKIs, such as osimertinib, rociletinib and olmutinib, showed a great activity. In this review, we summarize the scientific evidences about biology, evaluation and treatment on NSCLC with EGFR T790M mutation.

Update on recent preclinical and clinical studies of T790M mutant-specific irreversible epidermal growth factor receptor tyrosine kinase inhibitors.

The first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (1/2G EGFR-TKIs) gefitinib, erlotinib, and afatinib have all been approved as standard first-line treatments for advanced EGFR mutation-positive non-small cell lung cancer. The third-generation (3G) EGFR-TKIs have been developed to overcome the EGFR T790M mutation, which is the most common mechanism of acquired resistance to 1/2G EGFR-TKI treatment. This resistance mutation develops in half of the patients who respond to 1/2G EGFR-TKI therapy. The structures of the novel 3G EGFR-TKIs are different from those of 1/2G EGFR-TKIs. Particularly, 3G EGFR-TKIs have lower affinity to wild-type EGFR, and are therefore associated with lower rates of skin and gastrointestinal toxicities. However, many of the adverse events (AEs) that are observed in patients receiving 3G EGFR-TKIs have not been observed in patients receiving 1/2G EGFR-TKIs. Although preclinical studies have revealed many possible mechanisms for these AEs, the causes of some AEs remain unknown. Many mechanisms of resistance to 3G EGFR-TKI therapy have also been reported. Here, we have reviewed the recent clinical and preclinical developments related to novel 3G EGFR-TKIs, including osimertinib, rociletinib, olmutinib, EGF816, and ASP8273.

The impacts of CYP3A4 genetic polymorphism and drug interactions on the metabolism of lurasidone.

The aim of this study was to investigate the impacts of 24 variants of recombinant human CYP3A4 and drug interactions on the metabolism of lurasidone. In vitro, enzymatic reaction incubation system of CYP3A4 was established to determine the kinetic parameters of lurasidone catalyzed by 24 CYP3A4 variants. Then, we constructed rat liver microsomes (RLM) and human liver microsomes (HLM) incubation system to screen potential anti-tumor drugs that could interact with lurasidone and studied its inhibitory mechanism. In vivo, Sprague-Dawley (SD) rats were applied to study the interaction between lurasidone and olmutinib. The concentrations of the analytes were detected by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). As the results, we found that compared with the wild-type CYP3A4, the relative intrinsic clearances vary from 355.77 % in CYP3A4.15 to 14.11 % in CYP3A4.12. A series of drugs were screened based on the incubation system, and compared to without olmutinib, the amount of ID-14283 (the metabolite of lurasidone) in RLM and HLM were reduced to 7.22 % and 7.59 %, and its IC50 were 18.83 ± 1.06 µM and 16.15 ± 0.81 µM, respectively. At the same time, it exerted inhibitory effects both through a mixed mechanism. When co-administration of lurasidone with olmutinib in rats, the AUC(0-t) and AUC(0-∞) of lurasidone were significantly increased by 73.52 % and 69.68 %, respectively, while CLz/F was observably decreased by 43.83 %. In conclusion, CYP3A4 genetic polymorphism and olmutinib can remarkably affect the metabolism of lurasidone.

Elucidation of the interaction mechanism of olmutinib with human α-1 acid glycoprotein: insights from spectroscopic and molecular modeling studies.

Olmutinib, the third-generation tyrosine kinase inhibitor, is applied in treating non-small cell lung cancer (NSCLC). The aim of this study is to elucidate the interaction mechanism of olmutinib with human α-1 acid glycoprotein (HAG), an important carrier protein, by mean of multi-spectroscopic and molecular simulation techniques. Fluorescence spectral results confirmed that the fluorescence of this carrier protein can be quenched by olmutinib in the static quenching mode, and this anticancer drug possesses a moderate binding affinity on HAG. The evidence from thermodynamic analysis, replacement interaction with ANS and sucrose, and computational simulation results showed that hydrogen bonding, hydrophobic interactions, and van der Waals forces involved the olmutinib-HAG complexation process. The results from UV-vis, 3D fluorescence and synchronous fluorescence spectroscopy proved that binding anticancer drug olmutinib caused the alteration in the microenvironment around Trp residues. And, circular dichroism spectral results provided the support for the conformational alterations in the carrier protein. The data also proved that olmutinib preferably bound to the hydrophobic cavity of HAG and the binding distance between the two was 2.21 nm. In addition, it can be found that the presence of some metal ions such as Zn2+, Ca2+, Ni2+ and Cu2+ would exert a certain extent effect on the olmutinib-HAG complexation process.Communicated by Ramaswamy H. Sarma.

Evaluation of the Effect of Wheat Germ Oil and Olmutinib on the Thioacetamide-Induced Liver and Kidney Toxicity in Mice.

Thioacetamide (TAA) intoxication produces a reproducible standard animal model of induced liver and kidney injuries where free radicals are produced by phase I oxidation reactions, which eventually leads to liver and kidney failure. Wheat germ oil (WGO) is a unique food supplement with concentrated nutrient efficiency and has remarkable antioxidant functions. Olmutinib, on the other hand, is a chemotherapy drug considered safe for kidneys and the liver. Therefore, in this study, WGO and olmutinib were investigated for their effect on TAA-induced liver and kidney damage. Inflammatory markers; interleukin-1 beta (IL-1ß); IL-6; and the levels of enzymatic markers ALT (Alanine aminotransferase), AST (Aspartate aminotransferase), LDH (Lactate dehydrogenase), and CK (creatinine kinase) in serum for liver and kidney were analyzed and evaluated along with histopathological changes in the tissue. Thirty male mice 4-6 weeks of age were grouped into five groups of six animals: the control group (saline) and the other groups (Groups II to V), which were given thioacetamide for two weeks. In addition, Group II continued with TAA; Group III was given olmutinib (30 mg/kg), Group IV was given the wheat germ oil (WGO) (1400 mg/kg), and Group V was given (olmutinib (30 mg/kg) + WGO (1400 mg/kg)) for five days. The results suggested that olmutinib treatment potentiated TAA-induced liver and kidney injury. At the same time, WGO efficiently alleviated TAA and TAA-olmutinib toxicity in Groups IV and V. The histological studies also showed reduced damage with WGO in the animal model. Hence, it was concluded that WGO could significantly reduce liver and kidney damage caused by TAA and olmutinib in mice.

Spectroscopic, molecular docking and dynamic simulation studies of binding between the new anticancer agent olmutinib and human serum albumin.

In this study, the interaction between human serum albumin (HSA), which is the key bio-distributor of exogenous and endogenous compounds in the human bloodstream, and HM61713 (Olmutinib; OMB), which is used as an anticancer drug, is examined by multiple spectroscopic techniques (steady-state fluorescence, UV spectrophotometry, synchronous, and 3 D fluorescence) combined with molecular docking and molecular dynamic simulation investigations. The fluorescence results clearly demonstrated quenching in HSA fluorescence in the existence of OMB indicating the formation of complex and have also shown that the interaction is static. Fluorescence spectroscopy was used to obtain the binding constant values that revealed a strong interaction between the HSA and OMB at 298 K with a binding constant of 7.39x104 M-1 suggesting strong interaction. OMB binds to HSA at site I (IIA). Electrostatic forces and H-bonding were the main binding forces of main bonding between HSA and OMB as revealed by docking and thermodynamic results.Communicated by Ramaswamy H. Sarma.

A safety, pharmacokinetic, pharmacogenomic and population pharmacokinetic analysis of the third-generation EGFR TKI, olmutinib (HM61713), after single oral administration in healthy volunteers.

The main objective of this phase I trial was to investigate pharmacokinetics (PKs) of olmutinib in three racial subjects. We also evaluate safety/tolerability and a population PK and pharmacogenomic analysis were performed for explorative purposes. A dose escalation study was conducted in 56 Korean, Japanese and Caucasian subjects. The food effect was assessed in the 300 mg Korean group. Individual PK parameters were calculated by non-compartmental methods and presented by dose and race. Genotype analysis was performed using DMET® plus to identify genotypes which affect PK characteristics. A population PK model was developed to explore inter-individual variability and to evaluate the influence of possible covariates using NONMEM® . Tmax was 2-3 hour, regardless of race. The mean terminal half-life ranged from 4.8 to 7.4 hour, with no significant differences between dose or racial groups. Dose-normalized Cmax and AUClast were not significantly different between race groups. PK parameters were similar between the fasting and fed conditions. A single-nucleotide polymorphism in the GSTM3 gene (rs4783) and a copy number variation in the GSTM1 gene were significantly related to AUC. A one-compartment model with first-order absorption adequately described the observed olmutinib data. Thirty adverse events were observed in 15 subjects, of which 26 events, all mild, were possibly related to olmutinib. A single oral dose of olmutinib 100-300 mg was safe and well tolerated. PK parameters were dose-proportional and did not differ by race. Food intake did not affect olmutinib absorption. Pharmacogenomic analysis indicated that glutathione S-transferase might be involved in olmutinib metabolism.

Safety, tolerability, and anti-tumor activity of olmutinib in non-small cell lung cancer with T790M mutation: A single arm, open label, phase 1/2 trial.

OBJECTIVES: The aim of this phase 1/2 study was to evaluate the safety, tolerability, pharmacokinetics and antitumor activity of olmutinib in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who had failed ≥ 1 previous line of EGFR-tyrosine kinase inhibitor (TKI) therapy. MATERIALS AND METHODS: Phase 1 consisted of dose-escalation and four dose-expansion parts (1: olmutinib 300 mg once daily; 2A: 800 mg once daily [EGFR T790 M mutation-positive patients]; 2B: 500 mg twice daily [EGFR T790 M mutation-positive]; 3: 800 mg once daily [EGFR T790 M mutation-negative]). In phase 2, EGFR T790 M mutation-positive patients received olmutinib 800 mg once daily. Data from expansion part 2A and phase 2 were integrated (`pooled phase 2'). Each olmutinib cycle was 21 days. Outcomes included: tumor response, treatment-emergent adverse events (TEAEs), pharmacokinetic parameters. RESULTS: Overall, 272 patients received at least one olmutinib dose: dose-escalation (n = 66), expansion parts (n = 165), phase 2 (n = 41). In pooled phase 2, the overall objective response rate, confirmed by independent review, was 55.1% (38/69 evaluable patients; 95% CI, 42.6-67.1). All responses were partial responses; 23 patients had stable disease. Estimated median progression-free survival was 6.9 (95% CI, 5.6-9.7) months; estimated median overall survival was not reached. The most frequent treatment-related AEs were diarrhea (59.2% of patients), pruritus (42.1%), rash (40.8%), and nausea (39.5%). CONCLUSION: Olmutinib showed effective clinical activity with a manageable safety profile, indicating therapeutic potential for T790M-positive NSCLC patients who have failed ≥ 1 previous line of EGFR-TKI therapy.

Olmutinib Induced Lichen Planus Like Eruption.

Drug induced lichen planus like eruption is an uncommon cutaneous adverse effect of several drugs. This appears symmetric eruption of erythematous or violaceous plaques resembling lichen planus on the trunk and extremities. A 50-year-old male presented with scaly, violaceous plaques and dusky brown macules on whole body. For four months, the patient was treated with olmutinib, an oral, third-generation epidermal growth factor receptor-tyrosine kinase inhibitor. In May 2016, olmutinib received its first global approval in South Korea for the treatment of patients with locally advanced or metastatic epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer. The biopsy specimen from the patient showed features of lichen planus. We diagnosed him with olmutinib-induced lichen planus like eruption. He was treated with oral methylprednisolone and topical desoxymethasone 0.25% ointment. At the same time, olmutinib dose was decreased to three-fourths of this patient's starting dose. After that, the cutaneous lesions improved.

Olmutinib (BI1482694/HM61713), a Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Reverses ABCG2-Mediated Multidrug Resistance in Cancer Cells.

The main characteristic of tumor cell resistance is multidrug resistance (MDR). MDR is the principle cause of the decline in clinical efficacy of chemotherapeutic drugs. There are several mechanisms that could cause MDR. Among these, one of the most important mechanisms underlying MDR is the overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) super-family of transporters, which effectively pump out cytotoxic agents and targeted anticancer drugs across the cell membrane. In recent years, studies found that ABC transporters and tyrosine kinase inhibitors (TKIs) interact with each other. TKIs may behave as substrates or inhibitors depending on the expression of specific pumps, drug concentration, their affinity for the transporters and types of co-administered agents. Therefore, we performed in vitro experiments to observe whether olmutinib could reverse MDR in cancer cells overexpressing ABCB1, ABCG2, or ABCC1 transporters. The results showed that olmutinib at 3 µM significantly reversed drug resistance mediated by ABCG2, but not by ABCB1 and ABCC1, by antagonizing the drug efflux function in ABCG2-overexpressing cells. In addition, olmutinib at reversal concentration affected neither the protein expression level nor the localization of ABCG2. The results observed from the accumulation/efflux study of olmutinib showed that olmutinib reversed ABCG2-mediated MDR with an increasing intracellular drug accumulation due to inhibited drug efflux. We also had consistent results with the ATPase assay that olmutinib stimulated ATPase activity of ABCG2 up to 3.5-fold. Additionally, the molecular interaction between olmutinib and ABCG2 was identified by docking simulation. Olmutinib not only interacts directly with ABCG2 but also works as a competitive inhibitor of the transport protein. In conclusion, olmutinib could reverse ABCG2-mediated MDR. The reversal effect of olmutinib on ABCG2-mediated MDR cells is not due to ABCG2 expression or intracellular localization, but rather related to its interaction with ABCG2 protein resulting in drug efflux inhibition and ATPase stimulation.

Olmutinib (HM61713) reversed multidrug resistance by inhibiting the activity of ATP-binding cassette subfamily G member 2 in vitro and in vivo.

Overexpressing of ATP-binding cassette (ABC) transporters is the essential cause of multidrug resistance (MDR), which is a significant hurdle to the success of chemotherapy in many cancers. Therefore, inhibiting the activity of ABC transporters may be a logical approach to circumvent MDR. Olmutinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which has been approved in South Korea for advanced EGFR T790M-positive non-small cell lung cancer (NSCLC). Here, we found that olmutinib significantly increased the sensitivity of chemotherapy drug in ABCG2-overexpressing cells. Furthermore, olmutinib could also increase the retention of doxorubicin (DOX) and rhodamine 123 (Rho 123) in ABC transporter subfamily G member 2 (ABCG2)-overexpressing cells. In addition, olmutinib was found to stimulate ATPase activity and inhibit photolabeling of ABCG2 with [125I]-iodoarylazidoprazosin (IAAP). However, olmutinib neither altered ABCG2 expression at protein and mRNA levels nor blocked EGFR, Her-2 downstream signaling of AKT and ERK. Importantly, olmutinib enhanced the efficacy of topotecan on the inhibition of S1-MI-80 cell xenograft growth. All the results suggest that olmutinib reverses ABCG2-mediated MDR by binding to ATP bind site of ABCG2 and increasing intracellular chemotherapeutic drug accumulation. Our findings encouraged to further clinical investigation on combination therapy of olmutinib with conventional chemotherapeutic drugs in ABCG2-overexpressing cancer patients.

Third generation EGFR TKIs in EGFR-mutated NSCLC: Where are we now and where are we going.

The therapeutic landscape of Non Small Lung Cancer (NSCLC) has been profoundly changed over the last decade with the clinical introduction of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) and the discovery of EGFR activating mutations as the major predictive factor to these agents. Despite impressive clinical activity against EGFR-mutated NSCLCs, the benefit seen with 1st and 2nd generation EGFR TKIs is usually transient and virtually all patients become resistant. Several different mechanisms of acquired resistance have been reported to date, but the vast majority of patients develop a secondary exon 20 mutation in the ATP-binding site of EGFR, namely T790M. The discovery of mutant-selective EGFR TKIs that selectively inhibit EGFR-mutants, including T790M-harboring NSCLCs, while sparing EGFR wild type, provide the opportunity for overcoming the major mechanism of acquired resistance to 1st and 2nd generation EGFR TKIs, with a relatively favorable toxicity profile. The development of this novel class of EGFR inhibitors poses novel challenges in the rapidly evolving therapeutic paradigm of EGFR-mutated NSCLCs and the next few years will witness the beginning of a new era for EGFR inhibition in lung cancer. The aim of this paper is to provide a comprehensive overview of the increasing body of data emerging from the ongoing clinical trials with this promising novel therapeutic class of EGFR inhibitors.