Synthetic Routes and Clinical Application of Representative Small-Molecule EGFR Inhibitors for Cancer Therapy.

The epidermal growth factor receptor (EGFR) plays a pivotal role in cancer therapeutics, with small-molecule EGFR inhibitors emerging as significant agents in combating this disease. This review explores the synthesis and clinical utilization of EGFR inhibitors, starting with the indispensable role of EGFR in oncogenesis and emphasizing the intricate molecular aspects of the EGFR-signaling pathway. It subsequently provides information on the structural characteristics of representative small-molecule EGFR inhibitors in the clinic. The synthetic methods and associated challenges pertaining to these compounds are thoroughly examined, along with innovative strategies to overcome these obstacles. Furthermore, the review discusses the clinical applications of FDA-approved EGFR inhibitors such as erlotinib, gefitinib, afatinib, and osimertinib across various cancer types and their corresponding clinical outcomes. Additionally, it addresses the emergence of resistance mechanisms and potential counterstrategies. Taken together, this review aims to provide valuable insights for researchers, clinicians, and pharmaceutical scientists interested in comprehending the current landscape of small-molecule EGFR inhibitors.

PDZK1 suppresses TNBC development and sensitizes TNBC cells to erlotinib via the EGFR pathway.

Epidermal growth factor receptor (EGFR)-targeted drugs (erlotinib, etc.) are used to treat multiple types of tumours. EGFR is highly expressed in most triple-negative breast cancer (TNBC) patients. However, only a small proportion of TNBC patients benefit from EGFR-targeted drugs in clinical trials, and the resistance mechanism is unclear. Here, we found that PDZ domain containing 1 (PDZK1) is downregulated in erlotinib-resistant TNBC cells, suggesting that PDZK1 downregulation is related to erlotinib resistance in TNBC. PDZK1 binds to EGFR. Through this interaction, PDZK1 promotes EGFR degradation by enhancing the binding of EGFR to c-Cbl and inhibits EGFR phosphorylation by hindering EGFR dimerisation. We also found that PDZK1 is specifically downregulated in TNBC tissues and correlated with a poor prognosis in TNBC patients. In vitro and in vivo functional assays showed that PDZK1 suppressed TNBC development. Restoration of EGFR expression or kinase inhibitor treatment reversed the degree of cell malignancy induced by PDZK1 overexpression or knockdown, respectively. PDZK1 overexpression sensitised TNBC cells to erlotinib both in vitro and in vivo. In conclusion, PDZK1 is a significant prognostic factor for TNBC and a potential molecular therapeutic target for reversing erlotinib resistance in TNBC cells.

Severe megaloblastic anemia in a patient with advanced lung adenocarcinoma during treatment with erlotinib: a case report and literature review.

BACKGROUND: Erlotinib is a first-generation, tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) used for the treatment patients with NSCLC. Erlotinib is considered as a safe and effective treatment option, with generally good tolerance. Diarrhea and rash are the most common side effects, and more rare side effects appear in long-term real-world applications. Severe erlotinib related megaloblastic anemia is rare and remains unreported. This is the first case report of severe megaloblastic anemia in a patient with advanced lung adenocarcinoma with an EGFR L858R mutation treated with erlotinib. In this report, the clinical manifestations, diagnosis and treatment of erlotinib related severe megaloblastic anemia are described, and the possible pathogenesis and related treatment options are discussed. CASE DESCRIPTION: Herein, we present a 57- year-old non-smoking female diagnosed with metastatic lung adenocarcinoma harboring an EGFR L858R mutation, who had received erlotinib as the first-line therapy. After 44 weeks of treatment, the patient developed severe anemia. Anemia was manifested as megaloblastic anemia with elevated mean corpuscular volume and mean corpuscular hemoglobin. The total vitamin B12 level was below the detection limit of 50.00 pg /mL. Bone marrow smear suggested megaloblastic anemia. Her hematologic parameters were markedly recovered following the withdrawal of erlotinib and vitamin B12 supplement. As a result, the patient was diagnosed with erlotinib-associated megaloblastic anemia. CONCLUSIONS: This is the first case of severe megaloblastic anemia reported with erlotinib. Few of these hematologic adverse effects have been observed in studies on erlotinib, this case report highlights this possibility for long-term erlotinib administration. Close clinical and blood monitoring is recommended for patients receiving long-term TKI therapy.

Humanization of SLCO2B1 in Rats Increases rCYP3A1 Protein Expression but Not the Metabolism of Erlotinib to OSI-420.

The organic anion transporting polypeptide (OATP)2B1 [(gene: solute carrier organic anion transporter family member 2B1 (SLCO2B1)] is an uptake transporter that facilitates cellular accumulation of its substrates. Comparison of SLCO2B1+/+ knockin and rSlco2b1-/- knockout rats showed a higher expression of rCYP3A1 in the humanized animals. We hypothesize that humanization of OATP2B1 not only affects cellular uptake but also metabolic activity. To further investigate this hypothesis, we used SLCO2B1+/+ and rSlco2b1-/ - rats and the OATP2B1 and rCYP3A1 substrate erlotinib, which is metabolized to OSI-420, for in vivo and ex vivo experiments. One hour after administration of a single dose of erlotinib, the knockin rats exhibited significantly lower erlotinib serum levels, but no change was observed in metabolite concentration or the OSI-420/erlotinib ratio. Similar results were obtained for liver tissue levels comparing SLCO2B1+/+ and rSlco2b1-/- rats. Liver microsomes isolated from the erlotinib-treated animals were characterized ex vivo for rCYP3A activity using testosterone, showing higher activity in the knockin rats. The contrary was observed when microsomes isolated from treatment-naïve animals were assessed for the metabolism of erlotinib to OSI-420. The latter is in contrast to the higher rCYP3A1 protein amount observed by western blot analysis in rat liver lysates and liver microsomes isolated from untreated rats. In summary, rats humanized for OATP2B1 showed higher expression of rCYP3A1 in liver and reduced serum levels of erlotinib but no change in the OSI-420/erlotinib ratio despite a lower OSI-420 formation in isolated liver microsomes. Studies with CYP3A-specific substrates are warranted to evaluate whether humanization affects not only rCYP3A1 expression but also metabolic activity in vivo. SIGNIFICANCE STATEMENT: Humanization of rats for the organic anion transporting polypeptide (OATP)2B1 increases rCYP3A1 expression and activity in liver. Using the OATP2B1/CYP3A-substrate erlotinib to assess the resulting phenotype, we observed lower erlotinib serum and liver concentrations but no impact on the liver/serum ratio. Moreover, there was no difference in the OSI-420/erlotinib ratio comparing humanized and knockout rats, suggesting that OSI-420 is not applicable to monitor differences in rCYP3A1 expression as supported by data from ex vivo experiments with rat liver microsomes.

Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival.

BACKGROUND: Pancreatic cancer is a leading cause of cancer-related deaths. Increased activity of the epidermal growth factor receptor (EGFR) is often observed in pancreatic cancer, and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration. Nevertheless, erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes. We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential (Δψm), facilitate tumor cell uptake of Δψm-sensitive agents, disrupt mitochondrial homeostasis, and subsequently trigger tumor cell death. Erlotinib has not been tested for this effect. AIM: To determine whether erlotinib can elevate Δψm and increase tumor cell uptake of Δψm-sensitive agents, subsequently triggering tumor cell death. METHODS: Δψm-sensitive fluorescent dye was used to determine how erlotinib affects Δψm in pancreatic adenocarcinoma (PDAC) cell lines. The viability of conventional and patient-derived primary PDAC cell lines in 2D- and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone (MitoQ), a Δψm-sensitive MitoQ. The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0. The preclinical efficacy of the two-drug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts. RESULTS: Erlotinib elevated Δψm in PDAC cells, facilitating tumor cell uptake and mitochondrial enrichment of Δψm-sensitive agents. MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses, while erlotinib pretreatment potentiated low doses of MitoQ. SynergyFinder suggested that these drugs synergistically induced tumor cell lethality. Consistent with in vitro data, erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent. CONCLUSION: Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.

Monolayer culture alters EGFR inhibitor response through abrogation of microRNA-mediated feedback regulation.

Ex vivo drug screening is a potentially powerful tool for the future of cancer care, but the accuracy of results is contingent on the culture model. Both monolayer (2D) and spheroid (3D) culture systems offer advantages, but given the differences in mechanical environment, we hypothesized that that the suitability of one system over another would be critical for screening drugs with mechanical targets in mechanical tissues. HCC827 lung adenocarcinoma cells were challenged with EGFR tyrosine kinase inhibitors in monolayer and spheroid culture. RNA sequencing was performed on cells in both conditions to assess culture-induced transcriptional changes that could account for differences in drug response and differences in EGFR expression detected by immunostain. A microRNA microarray was performed to assess culture-induced differences in regulation of microRNA, and the impact of miR-146a-5p on drug response was verified by inhibition. Results were confirmed in human lung adenocarcinoma tissue. HCC827 spheroids were resistant to erlotinib and gefitinib, but significantly more sensitive in 2D culture. RNA-seq and immunostaining show a discrepancy in EGFR transcript and protein expression between the two conditions, which we attribute to miR-146a-5p. This microRNA targets EGFR and is differentially expressed between 2D and 3D culture. Inhibition of miR-146a-5p significantly increased erlotinib cytotoxicity, but validation in patient-derived spheroids suggests that the effect may be mutation-specific. Analysis of RNA-seq data suggests that cells in 2D culture become highly dependent on EGFR signaling to drive proliferation and cell spreading, resulting in a misleading level of sensitivity to EGFR TKIs, while the same cells in spheroid culture retain microRNA-driven EGFR feedback regulation that leaves them less vulnerable to EGFR inhibition. These findings underscore the need for close scrutiny of culture-induced effects on drug target regulation in model design for ex vivo drug screening.

Development of erlotinib-loaded nanotransferosomal gel for the topical treatment of ductal carcinoma in situ.

Aims: This study was aimed to formulate erlotinib (ERL)-loaded transferosomal gel (ERL@TG) intended for topical application for the treatment of ductal carcinoma in situ. Materials & methods: The optimized process involved a thin-film hydration method to generate ERL-loaded transferosomes (ERL@TFS), which was incorporated into a carbopol gel matrix to generate ERL@TG. The optimized formulation was characterized in vitro followed by cytotoxicity evaluation on MCF-7 breast cancer cell lines and acute toxicity and skin irritation studies was performed in vivo. Results: In a comparative assessment against plain ERL, ERL@TG displayed enhanced efficacy against MCF-7 cell lines, reflected in considerably lower IC50 values with an enhanced safety profile. Conclusion: Optimized ERL@TG was identified as a promising avenue for addressing ductal carcinoma in situ breast cancer.

Despite progress, breast cancer remains a significant cause of death. This study aimed to revolutionize the treatment of noninvasive ductal carcinoma in situ, a type of breast cancer, by developing a special gel that can be applied directly to the breast. The developed gel was in the nanoform, a 'nanotransfersomal' gel that contained erlotinib, a potent drug for breast cancer. To ensure its effectiveness, we evaluated the erlotinib-loaded transfersomal gel through various tests. The results confirmed that the gel was nano-sized and loaded with a high amount of erlotinib. Animal studies were conducted to check if the prepared gel caused any skin irritation and interestingly, there was no irritation observed on the animals' skin. Furthermore, we treated breast cancer cells with the developed gel using a method called MTT assay and the results showed improved cell-killing activity in comparison to plain drug. In conclusion, this special gel represents a breakthrough in breast cancer treatment. It offers hope for better outcomes in the fight against this disease. This innovative approach involves directly applying the gel on the affected area topically to increase patient compliance and decreasing side effects of drugs. This could potentially transform ductal carcinoma in situ breast cancer treatment, bringing us closer to improved treatments and outcomes.

Association of systemic inflammatory markers with prognosis in erlotinib-treated EGFR-mutant non-small cell lung cancer.

BACKGROUND: To evaluate the relationship of overall survival (OS) and progression-free survival (PFS) with the derived neutrophil-lymphocyte ratio (dNLR), neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), and platelet-lymphocyte ratio (PLR) in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). METHODS: The study included 43 patients with EGFR-mutant metastatic NSCLC. The dNLR, NLR, LMR, and PLR values were calculated using the baseline complete blood counts before and after treatment with erlotinib. RESULTS: The NLR value had the best diagnostic test performance with a sensitivity of 91.3%. dNLR, NLR, LMR, and PLR were found to be significant for the prediction of OS and PFS. While the delta dNLR and NLR values were significant for OS, only the delta NLR value was significant for PFS. CONCLUSIONS: The dNLR, NLR, LMR, and PLR values were found to be significant in the prediction of OS and PFS in erlotinib-treated metastatic NSCLC. Further clinical studies are needed to determine the ideal target-specific tyrosine kinase inhibitor in cases of metastatic NSCLC presenting with the EGFR-activating mutation.

Design, synthesis, in silico molecular docking, and ADMET studies of quinoxaline-isoxazole-piperazine conjugates as EGFR-targeting agents.

In this paper, we report the synthesis of quinoxaline-isoxazole-piperazine conjugates. The anticancer activity was evaluated against three human cancer cell lines, including MCF-7 (breast), HepG-2 (liver), and HCT-116 (colorectal). The outcomes of the tested compounds 5d, 5e, and 5f have shown more potent activity when compared to the standard drug erlotinib. In a cell survivability test (MCF-10A), three potent compounds (5d, 5e, and 5f) were evaluated against the normal breast cell line, although neither of them displayed any significant cytotoxicity with IC50 values greater than 84 µM. Furthermore, the compounds 5d, 5e, and 5f were tested for tyrosine kinase EGFR inhibitory action using erlotinib as the reference drug and compound 5e was shown to be more potent in inhibiting the tyrosine kinase EGFR than sorafenib. In addition to this, molecular docking studies of compounds 5d, 5e, and 5f demonstrated that these compounds had more EGFR-binding interactions. The potent compounds 5d, 5e, and 5f were subjected to in silico pharmacokinetic assessment by SWISS, ADME, and pkCSM. While the compounds 5d, 5e, and 5f followed Lipinski, Veber, Egan, and Muegge rules without any deviation.

Activation of the PI3K/AKT signaling pathway by ARNTL2 enhances cellular glycolysis and sensitizes pancreatic adenocarcinoma to erlotinib.

BACKGROUND: Pancreatic adenocarcinoma (PC) is an aggressive malignancy with limited treatment options. The poor prognosis primarily stems from late-stage diagnosis and when the disease has become therapeutically challenging. There is an urgent need to identify specific biomarkers for cancer subtyping and early detection to enhance both morbidity and mortality outcomes. The addition of the EGFR tyrosine kinase inhibitor (TKI), erlotinib, to gemcitabine chemotherapy for the first-line treatment of patients with advanced pancreatic cancer slightly improved outcomes. However, restricted clinical benefits may be linked to the absence of well-characterized criteria for stratification and dependable biomarkers for the prediction of treatment effectiveness. METHODS AND RESULTS: We examined the levels of various cancer hallmarks and identified glycolysis as the primary risk factor for overall survival in PC. Subsequently, we developed a glycolysis-related score (GRS) model to accurately distinguish PC patients with high GRS. Through in silico screening of 4398 compounds, we discovered that erlotinib had the strongest therapeutic benefits for high-GRS PC patients. Furthermore, we identified ARNTL2 as a novel prognostic biomarker and a predictive factor for erlotinib treatment responsiveness in patients with PC. Inhibition of ARNTL2 expression reduced the therapeutic efficacy, whereas increased expression of ARNTL2 improved PC cell sensitivity to erlotinib. Validation in vivo using patient-derived xenografts (PDX-PC) with varying ARNTL2 expression levels demonstrated that erlotinib monotherapy effectively halted tumor progression in PDX-PC models with high ARNTL2 expression. In contrast, PDX-PC models lacking ARNTL2 did not respond favorably to erlotinib treatment. Mechanistically, we demonstrated that the ARNTL2/E2F1 axis-mediated cellular glycolysis sensitizes PC cells to erlotinib treatment by activating the PI3K/AKT signaling pathway. CONCLUSIONS: Our investigations have identified ARNTL2 as a novel prognostic biomarker and predictive indicator of sensitivity. These results will help to identify erlotinib-responsive cases of PC and improve treatment outcomes. These findings contribute to the advancement of precision oncology, enabling more accurate and targeted therapeutic interventions.

Pancreatic adenocarcinoma third line systemic treatments: a retrospective cohort study.

BACKGROUND: Chemotherapy for metastatic pancreatic adenocarcinoma (PDAC) primarily relies on FOLFIRINOX (LV5FU- irinotecan - Oxaliplatine) and Gemcitabine - Nab-Paclitaxel in the first-line setting. However, second-lines remain less well-defined and there is limited data regarding third-line treatments. The objective of our study was to determine the proportion of patients advancing to third line chemotherapy, to outline the various third-line chemotherapy regimens used in routine practice and to evaluate their respective efficacy. METHODS: A retrospective single-center cohort from 2010-2022 compiled baseline characteristics, treatment outcomes and survival of PDAC patients who received at least one chemotherapy line in a French tertiary-center. Overall survivals (OS) were analyzed using a Cox multivariable model. RESULTS: In total, 676 patients were included, with a median follow-up time of 69.4 months, (Interquartile Range (IQR) = 72.1). Of these, 251 patients (37%) that proceeded to 3rd-line chemotherapy. The median PFS in 3rd line was 2.03 months, [CI95%: 1.83, 2.36]. The median 3rd line overall survival was 5.5 months, [CI95%: 4.8, 6.3]. In multivariable analysis erlotinib-based chemotherapy was found to be deleterious (HR=2.38, [CI95%: 1.30, 4.34], p=0.005) compared to fluoropyrimidine-based chemotherapy in terms of 3rd line overall survival while gemcitabine monotherapy showed a tendency towards negative outcomes. First and 2nd line chemotherapies sequence didn't influence 3rd line outcome. CONCLUSION: In our cohort, one-third of treated patients proceeded to 3rd line chemotherapy resulting in a 5.5 months median 3rd line OS, consistent with treatments at advanced stage. Our results argue against the use of erlotinib and gemcitabine monotherapy.

Dendritic cell vaccination in combination with erlotinib in a patient with inoperable lung adenocarcinoma: a case report.

BACKGROUND: Satisfactory treatment for patients with unresectable advanced lung cancer has not yet been established. We report a case of unresectable advanced lung cancer (stage IIIb: T2aN3M0) treated with a total of 15 doses of dendritic cells pulsed with a Wilms' tumor 1 and mucin 1 vaccine in combination with erlotinib, a small molecule epidermal growth factor receptor tyrosine kinase inhibitor, for more than 699 days without recurrence or metastasis. CASE PRESENTATION: A 63-year-old Korean woman was diagnosed with lung adenocarcinoma by pathology and computed tomography. The adenocarcinoma showed an epidermal growth factor receptor (EGFR) mutation, no anaplastic lymphoma kinase expression, and less than 1% expression of programmed death ligand 1. She received erlotinib alone for approximately 1 month. She then received erlotinib and the dendritic cells pulsed with Wilms' tumor 1 and mucin 1 vaccine. The diameter of the erythema at the vaccinated sites was 30 mm at 48 hours after the first vaccination. Moreover, it was maintained at more than 20 mm during the periods of vaccination. These results suggested the induction of antitumor immunity by the vaccine. Remarkably, the tumor size decreased significantly to 12 mm, a 65.7% reduction, after combined therapy with eight doses of the dendritic cells pulsed with Wilms' tumor 1 and mucin 1 vaccine and erlotinib for 237 days based on fluorodeoxyglucose uptake by positron emission tomography/computed tomography and computed tomography. Interestingly, after 321 days of combination therapy, the clinical findings improved, and no tumor was detected based on computed tomography. Validation of the tumor's disappearance persisted for at least 587 days after treatment initiation, without any indication of recurrence or metastasis. CONCLUSION: Standard anticancer therapy combined with the dendritic cells pulsed with Wilms' tumor 1 and mucin 1 vaccine may have therapeutic effects for such patients with unresectable lung adenocarcinoma.

The role of angiogenesis inhibitors associated with tyrosine kinase inhibitors in the first-line treatment for EGFR-mutated advanced lung cancer.

Tyrosine kinase inhibitors (TKIs) are the standard treatment for epidermal growth factor receptor mutant (EGFRm) advanced non-small cell lung cancer (NSCLC). Combining TKIs with an angiogenesis inhibitor has shown promise in pre-clinical studies. A systematic search of clinical trials found that combining erlotinib (a first-generation TKI) with bevacizumab or ramucirumab (angiogenesis inhibitors) improved progression-free survival (PFS) in EGFRm advanced NSCLC patients compared to TKI alone. However, no significant benefit in overall survival (OS) was observed in trials. Similar efficacy was seen in patients with specific EGFR mutations. Third generation TKIs were used as second-line therapy for patients with the T790M mutation. The combination treatment was associated with a higher incidence of severe adverse events. Overall, combining erlotinib or another TKI with an angiogenesis inhibitor is a safe and effective alternative for first-line treatment in EGFRm advanced NSCLC, particularly in countries without access to osimertinib and for patients with the EGFR L858R mutation.

Mechanism of action of adapalene for treating EGFR-TKI-induced skin disorder.

BACKGROUND: Skin disorders are the most common side effect associated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. It is important to manage skin lesions. Adapalene has been used to treat skin lesions caused by EGFR-TKIs in some cases. The aim of this study was to investigate the functional mechanism of adapalene in erlotinib-induced skin disorder. METHODS: To analyze the effect of adapalene on skin rash, afatinib and adapalene were administered to mice. The relationship between the concentration of adapalene and skin disorders was also examined by analyzing AQP3 expression. A skin lesion model was experimentally established in human skin keratinocytes (HaCaT) by using erlotinib with TNF-α and IL-1ß. We used qRT-PCR to analyze chemokine-induced inflammation and western blotting to analyze the effects of adapalene on the NF-κB signaling pathway. Antimicrobial peptides and adhesion factors were also examined using qRT-PCR. RESULTS: Mice administered 0.01% adapalene had less skin inflammation than mice treated with afatinib alone. The expression level of AQP3 decreased in an adapalene concentration-dependent manner. The mRNA levels of proinflammatory cytokines such as CCL2 and CCL27 in HaCaT cells were significantly reduced by adapalene. The expression of an antimicrobial peptide, hBD3, was upregulated after adapalene treatment. Adhesion factors, such as E-cadherin, were significantly downregulated by EGFR-TKI and significantly upregulated by adapalene treatment. Western blot analysis suggested that erlotinib-induced phosphorylation of p65 was decreased by adapalene. CONCLUSION: We suggest that adapalene may be a possible treatment option for skin disorders induced by EGFR-TKIs.

Quantitative modeling of tumor dynamics and development of drug resistance in non-small cell lung cancer patients treated with erlotinib.

Insight into the development of treatment resistance can support the optimization of anticancer treatments. This study aims to characterize the tumor dynamics and development of drug resistance in patients with non-small cell lung cancer treated with erlotinib, and investigate the relationship between baseline circulating tumor DNA (ctDNA) data and tumor dynamics. Data obtained for the analysis included (1) intensively sampled erlotinib concentrations from 29 patients from two previous pharmacokinetic (PK) studies, and (2) tumor sizes, ctDNA measurements, and sparsely sampled erlotinib concentrations from 18 patients from the START-TKI study. A two-compartment population PK model was first developed which well-described the PK data. The PK model was subsequently applied to investigate the exposure-tumor dynamics relationship. To characterize the tumor dynamics, models accounting for intra-tumor heterogeneity and acquired resistance with or without primary resistance were investigated. Eventually, the model assumed acquired resistance only resulted in an adequate fit. Additionally, models with or without exposure-dependent treatment effect were explored, and no significant exposure-response relationship for erlotinib was identified within the observed exposure range. Subsequently, the correlation of baseline ctDNA data on EGFR and TP53 variants with tumor dynamics' parameters was explored. The analysis indicated that higher baseline plasma EGFR mutation levels correlated with increased tumor growth rates, and the inclusion of ctDNA measurements improved model fit. This result suggests that quantitative ctDNA measurements at baseline have the potential to be a predictor of anticancer treatment response. The developed model can potentially be applied to design optimal treatment regimens that better overcome resistance.

Design, synthesis, and apoptotic antiproliferative action of new 1,2,3-triazole/1,2,4-oxadiazole hybrids as dual EGFR/VEGFR-2 inhibitors.

A novel series of 1,2,3-triazole/1,2,4-oxadiazole hybrids (7a-o) was developed as dual inhibitors of EGFR/VEGFR-2. Compounds 7a-o were evaluated as antiproliferative agents with Erlotinib as the reference drug. Results demonstrated that most of the tested compounds showed significant antiproliferative action with GI50 values ranging from 28 to 104 nM, compared to Erlotinib (GI50 = 33 nM), and compounds 7i-m were the most potent. Compounds 7h, 7i, 7j, 7k, and 7l were evaluated as dual EGFR/VEGFR-2 inhibitors. These in vitro experiments demonstrated that compounds 7j, 7k, and 7l are potent antiproliferative agents that may operate as dual EGFR/VEGFR-2 inhibitors. Compounds 7j, 7k, and 7l were evaluated for their apoptotic potential activity, where findings indicated that compounds 7j, 7k, and 7l promote apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking simulations show the binding mode of the most active antiproliferative compounds within EGFR and VEGFR-2 active sites.

2-Thioxo-3,4-dihydropyrimidine and thiourea endowed with sulfonamide moieties as dual EGFRT790M and VEGFR-2 inhibitors: Design, synthesis, docking, and anticancer evaluations.

The effectiveness of a new series of thiopyrimidine and thiourea containing sulfonamides moieties was tested on HCT-116, MCF-7, HepG2, and A549. HepG2 cell line was the one that all the new derivatives affected the most. The greatest potent compounds against the four HepG2, HCT116, MCF-7, and A549 cell lines were 8f and 8g with IC50 = 4.13, 6.64, 5.74, 6.85 µM and 4.09, 4.36, 4.22, 7.25 µM correspondingly. Compound 8g exhibited higher activity than sorafenib against HCT116 and MCF-7 but exhibited lower activity against HepG2 and A549. Moreover, compounds 8f and 8g exhibited higher activities than erlotinib on HepG2, HCT116, and MCF-7 but demonstrated lower activity on A549. The most potent cytotoxic derivatives 6f, 6g, 8c, 8d, 8e, 8f, and 8g were examined on normal VERO cell lines. Our derivatives have low toxicity on VERO cells with IC50 values ranging from 32.05 to 53.15 µM. Additionally, all compounds were assessed for dual VEGFR-2 and EGFRT790M inhibition effects. Compounds 8f and 8g were the most potent derivatives inhibited VEGFR-2 at IC50 value of 0.88 and 0.90 µM, correspondingly. As well, derivatives 8f and 8g could inhibit EGFRT790M demonstrating strongest effects with IC50 = 0.32 and 0.33 µM sequentially. Additionally, the greatest active derivatives ADMET profile was evaluated in relationship with sorafenib and erlotinib as reference agents. The data attained from docking were greatly related to that achieved from the biological testing.

Hexane Fraction of Adenophora triphylla var. japonica Root Extract Inhibits Angiogenesis and Endothelial Cell-Induced Erlotinib Resistance in Lung Cancer Cells.

The aim of this study was to investigate the anti-angiogenic effects of the hexane fraction of Adenophora triphylla var. japonica root extract (HAT) and its influence on the development of erlotinib resistance in human lung cancer cells. HAT significantly reduced the migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs). The phosphorylation levels of vascular endothelial growth factor receptor 2 (VEGFR2) and its downstream molecules were decreased via HAT, indicating its anti-angiogenic potential in endothelial cells (ECs). A docking analysis demonstrated that ß-sitosterol and lupeol, representative components of HAT, exhibit a high affinity for binding to VEGFR2. In addition, conditioned media from HAT-pretreated H1299 human lung cancer cells attenuated cancer-cell-induced chemotaxis of HUVECs, which was attributed to the decreased expression of angiogenic and chemotactic factors in H1299 cells. Interestingly, co-culture of erlotinib-sensitive PC9 human lung cancer cells with HUVECs induced erlotinib resistance in PC9 cells. However, co-culture with HAT-pretreated HUVECs partially restored the sensitivity of PC9 cells to erlotinib. HAT inhibited the development of erlotinib resistance by attenuating hepatocyte growth factor (HGF) production by ECs. Taken together, our results demonstrate that HAT exerts its anticancer effects by regulating the crosstalk between ECs and lung cancer cells.

Mismatch Between Brain MRIs and 18 F-DOPA PET/CT : Impact on the Management of a Long Survivor With EGFR-Mutated Lung Adenocarcinoma.

ABSTRACT: After receiving erlotinib for 4 years, a man with advanced lung adenocarcinoma was treated with stereotactic radiotherapy for a left cerebellar brain metastasis. Local relapse of the metastasis was suspected 14 months after and confirmed on 18 F-DOPA PET. Three additional uptakes were described with no unequivocal MRI pathological signal. A second radiotherapy course was delivered. One year later, isolated local recurrence was suspected on a 3 T MRI, with a suspicious 18 F-DOPA uptake. Five additional 18 F-DOPA uptakes were described among which one increased between the 2 PETs. Because of these MRI/PET mismatches, a switch from erlotinib to osimertinib was preferred over surgery.

Self-Assembly of Erlotinib-Platinum(II) Complexes for Epidermal Growth Factor Receptor-Targeted Photodynamic Therapy.

Due to cell mutation and self-adaptation, the application of clinical drugs with early epidermal growth factor receptor (EGFR)-targeted inhibitors is severely limited. To overcome this limitation, herein, the synthesis and in-depth biological evaluation of an erlotinib-platinum(II) complex as an EGFR-targeted anticancer agent is reported. The metal complex is able to self-assemble inside an aqueous solution and readily form nanostructures with strong photophysical properties. While being poorly toxic toward healthy cells and upon treatment in the dark, the compound was able to induce a cytotoxic effect in the very low micromolar range upon irradiation against EGFR overexpressing (drug resistant) human lung cancer cells as well as multicellular tumor spheroids. Mechanistic insights revealed that the compound was able to selectively degrade the EGFR using the lysosomal degradation pathway upon generation of singlet oxygen at the EGFR. We are confident that this work will open new avenues for the treatment of EGFR-overexpressing tumors.