Only in Titles

Search results for: Dacomitinib (PF-00299804) Mechanisms: EGFR HER inhibitor

paperclip

#33941614   2021/05/03 To Up

Host-dependent Phenotypic Resistance to EGFR Tyrosine Kinase Inhibitors.

Lung cancers driven by mutant forms of the epidermal growth factor receptor (EGFR) invariably develop resistance to kinase inhibitors, often due to secondary mutations. Here we describe an unconventional mechanism of resistance to dacomitinib, a newly approved covalent EGFR kinase inhibitor, and uncover a previously unknown step of resistance acquisition. Dacomitinib-resistant derivatives of lung cancer cells were established by means of gradually increasing dacomitinib concentrations. These dacomitinib-resistant (DR) cells acquired no secondary mutations in the kinase or other domains of EGFR. Along with resistance to other EGFR inhibitors, DR cells acquired features characteristic to epithelial-mesenchymal transition, including an expanded population of aldehyde dehydrogenase (ALDH)-positive cells and upregulation of AXL, a receptor previously implicated in drug resistance. Unexpectedly, when implanted in animals, DR cells reverted to a dacomitinib-sensitive state. Nevertheless, cell lines derived from regressing tumors displayed renewed resistance when cultured in vitro. 3D and co-cultures along with additional analyses indicated lack of involvement of hypoxia, fibroblasts, and immune cells in phenotype reversal, implying that other host-dependent mechanisms might nullify non-mutational modes of resistance. Thus, similar to the phenotypic resistance of bacteria treated with antibiotics, the reversible resisters described here likely evolve from drug-tolerant persisters and give rise to the irreversible, secondary mutation-driven non-reversible resister state.
Yuya Haga, Ilaria Marrocco, Ashish Noronha, Mary Luz Uribe, Nishanth Belugali Nataraj, Arunachalam Sekar, Diana Drago-Garcia, Simone Borgoni, Moshit Lindzen, Suvendu Giri, Stefan Wiemann, Yasuo Tsutsumi, Yosef Yarden

2355 related Products with: Host-dependent Phenotypic Resistance to EGFR Tyrosine Kinase Inhibitors.

5 inhibitors100 ul0.1ml8 inhibitors100 ul100 ul200 ug100 ul50 ug 50ul (1mg/ml)50 ug 50 ug

Related Pathways

paperclip

#31803256   2019/11/25 To Up

Second-line treatment of T790M-negative non-small cell lung cancer patients.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the currently recommended treatment for advanced mutation-positive non-small cell lung cancer (NSCLC). Acquired resistance inevitably develops, with the T790M mutation comprising approximately 55% of the mechanisms of resistance following first- or second-generation EGFR-TKI therapy (e.g. gefitinib, erlotinib, afatinib, and dacomitinib). Patients without T790M are a heterogeneous group for whom platinum-based chemotherapy is currently recommended as a second-line treatment. In addition to secondary mutations in (e.g. T790M), the currently known resistance mechanisms can be classified into the following three categories: bypass pathways, downstream signaling pathways, and histologic transformations. Given the evolving knowledge and convenience of diagnosing acquired resistance mechanisms by next-generation sequencing and liquid biopsy, exploratory studies targeting these resistance mechanisms and incorporating immunotherapy into the treatment paradigm have become the mainstream of future development. This review focuses on acquired resistance mechanisms other than T790M that develop after first- or second-generation EGFR-TKI therapy. Exploratory second-line treatments targeting resistance mechanisms as well as combination immunotherapy and chemotherapy in ongoing clinical trials are reviewed here. We also highlight the recent development of next-generation sequencing and liquid biopsy in this field.
Bin-Chi Liao, Sebastian Griesing, James Chih-Hsin Yang

1193 related Products with: Second-line treatment of T790M-negative non-small cell lung cancer patients.



Related Pathways

paperclip

#31606604   2019/10/10 To Up

Inhibiting Pathways Predicted From a Steroid Hormone Gene Signature Yields Synergistic Antitumor Effects in NSCLC.

Mounting evidence supports a role for estrogen signaling in NSCLC progression. We previously reported a seven-gene signature that predicts prognosis in estrogen receptor β positive (ERβ+) NSCLC. The signature defines a network comprised of ER and human EGFR-2/3 (HER2/HER3) signaling.
Abdulaziz A Almotlak, Mariya Farooqui, Jill M Siegfried

2320 related Products with: Inhibiting Pathways Predicted From a Steroid Hormone Gene Signature Yields Synergistic Antitumor Effects in NSCLC.

96T300 units96 tests 100 UG20 96 assays4 Membranes/Box

Related Pathways

paperclip

#31356117   2019/08/05 To Up

Dacomitinib for the first-line treatment of patients with EGFR-mutated metastatic non-small cell lung cancer.

: Different EGFR tyrosine kinase inhibitors (TKIs) are currently approved for the first-line treatment of NSCLC patients with EGFR mutations. Dacomitinib is an orally administered, second-generation pan-HER inhibitor that has shown to improve PFS and OS compared to the first-generation TKI gefitinib and is the most recent inhibitor to be approved in this setting. : This article will review relevant literature regarding preclinical findings and clinical data from phase I-III trials of dacomitinib. We particularly discuss the mechanism of action of dacomitinib and its clinical efficacy and toxicity as a novel, first-line therapeutic option for EGFR-mutated NSCLC. : The therapeutic landscape for EGFR-mutated NSCLC has been greatly expanded. In the first-line setting, we have currently first-, second- and third-generation EGFR TKIs available and some combination strategies, including EGFR TKIs with anti-angiogenic drugs or chemotherapy, have also shown to be effective. However, more data are needed to define the optimal therapeutic sequencing of all these targeted agents and combinations. In this view, molecular profiling of tumor tissues and liquid biopsies may provide novel insights on mechanisms of resistance to different drugs and guide treatment decisions.
Mariacarmela Santarpia, Jessica Menis, Imane Chaib, Maria Gonzalez Cao, Rafael Rosell

2919 related Products with: Dacomitinib for the first-line treatment of patients with EGFR-mutated metastatic non-small cell lung cancer.



Related Pathways

paperclip

#31209328   2019/06/18 To Up

Dacomitinib, but not lapatinib, suppressed progression in castration-resistant prostate cancer models by preventing HER2 increase.

Despite overexpression of the ErbB (EGFR/HER2/ErbB3/ErbB4) family in castration-resistant prostate cancer (CRPC), some inhibitors of this family, including the dual EGFR/HER2 inhibitor lapatinib, failed in Phase II clinical trials. Hence, we investigated mechanisms of lapatinib resistance to determine whether alternate ErbB inhibitors can succeed.
Maitreyee K Jathal, Thomas M Steele, Salma Siddiqui, Benjamin A Mooso, Leandro S D'Abronzo, Christiana M Drake, Young E Whang, Paramita M Ghosh

1939 related Products with: Dacomitinib, but not lapatinib, suppressed progression in castration-resistant prostate cancer models by preventing HER2 increase.



Related Pathways

paperclip

#31025257   2019/04/25 To Up

The ERBB receptor inhibitor dacomitinib suppresses proliferation and invasion of pancreatic ductal adenocarcinoma cells.

Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is the fourth most common cause of cancer-related death in the USA. Local progression, early tumor dissemination and low efficacy of current treatments are the major reasons for its high mortality rate. The ERBB family is over-expressed in PDAC and plays essential roles in its tumorigenesis; however, single-targeted ERBB inhibitors have shown limited activity in this disease. Here, we examined the anti-tumor activity of dacomitinib, a pan-ERBB receptor inhibitor, on PDAC cells.
Majid Momeny, Fatemeh Esmaeili, Sepideh Hamzehlou, Hassan Yousefi, Sepehr Javadikooshesh, Vasimeh Vahdatirad, Zivar Alishahi, Seyedeh H Mousavipak, Davood Bashash, Ahmad R Dehpour, Seyyed M Tavangar, Javad Tavakkoly-Bazzaz, Peiman Haddad, Farzaneh Kordbacheh, Kamran Alimoghaddam, Ardeshir Ghavamzadeh, Seyed H Ghaffari

2358 related Products with: The ERBB receptor inhibitor dacomitinib suppresses proliferation and invasion of pancreatic ductal adenocarcinoma cells.

100ug50 ug 200ug100ug200ul100.00 ug100ug5mg100ug0.1 mg100 ug/vial

Related Pathways

paperclip

#30864018   2019/03/12 To Up

Strategies to overcome acquired resistance to EGFR TKI in the treatment of non-small cell lung cancer.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) represents a paradigm shift in the treatment of non-small cell lung cancer (NSCLC) patients and has been the first-line therapy in clinical practice. While erlotinib, gefitinib and afatinib have achieved superior efficacy in terms of progression-free survival and overall survival compared with conventional chemotherapy in NSCLC patients, most people inevitably develop acquired resistance to them, which presents another challenge in the treatment of NSCLC. The mechanisms of acquired resistance can be classified as three types: target gene mutation, bypass signaling pathway activation and histological transformation. And the most common mechanism is T790M which accounts for approximately 50% of all subtypes. Many strategies have been explored to overcome the acquired resistance to EGFR TKI. Continuation of EGFR TKI beyond progressive disease is confined to patients in asymptomatic stage when the EGFR addiction is still preserved in some subclones. While the combination of EGFR TKI and chemotherapy or other targeted agents has improved the survival benefit in EGFR TKI resistant patients, there are controversies within them. The next-generation EGFR TKI and immunotherapy represent two novel directions for overcoming acquired resistance and have achieved promising efficacy. Liquid biopsy provides surveillance of the EGFR mutation by disclosing the entire genetic landscape but tissue biopsy is still indispensable because of the considerable rate of false-negative plasma.
J Gao, H-R Li, C Jin, J-H Jiang, J-Y Ding

2471 related Products with: Strategies to overcome acquired resistance to EGFR TKI in the treatment of non-small cell lung cancer.

500 gm.

Related Pathways

paperclip

#30644426   2019/01/15 To Up

Genetically distinct glioma stem-like cell xenografts established from paired glioblastoma samples harvested before and after molecularly targeted therapy.

Intratumoural heterogeneity underlies tumour escape from molecularly targeted therapy in glioblastoma. A cell-based model preserving the evolving molecular profiles of a tumour during treatment is key to understanding the recurrence mechanisms and development of strategies to overcome resistance. In this study, we established a matched pair of glioblastoma stem-like cell (GSC) cultures from patient glioblastoma samples before and after epidermal growth factor receptor (EGFR)-targeted therapy. A patient with recurrent glioblastoma (MGG70R) harboring focal, high-level EGFR amplification received the irreversible EGFR tyrosine kinase inhibitor dacomitinib. The tumour that subsequently recurred (MGG70RR) showed diploid EGFR, suggesting inhibitor-mediated elimination of EGFR-amplified tumour cells and propagation of EGFR non-amplified cell subpopulations. The MGG70R-GSC line established from MGG70R formed xenografts retaining EGFR amplification and EGFR overexpression, while MGG70RR-GSC established from MGG70RR generated tumours that lacked EGFR amplification and EGFR overexpression. MGG70R-GSC-derived intracranial xenografts were more proliferative than MGG70RR-GSC xenografts, which had upregulated mesenchymal markers, mirroring the pathological observation in the corresponding patient tumours. In vitro MGG70R-GSC was more sensitive to EGFR inhibitors than MGG70RR-GSC. Thus, these molecularly distinct GSC lines recapitulated the subpopulation alteration that occurred during glioblastoma evasion of targeted therapy, and offer a valuable model facilitating therapeutic development for recurrent glioblastoma.
Shota Tanaka, Samantha Luk, Juri Kiyokawa, Maristela L Onozato, A John Iafrate, Khalid Shah, Robert L Martuza, Samuel D Rabkin, Tracy T Batchelor, Daniel P Cahill, Andrew S Chi, Hiroaki Wakimoto

1315 related Products with: Genetically distinct glioma stem-like cell xenografts established from paired glioblastoma samples harvested before and after molecularly targeted therapy.

1 kit(96 Wells)96 samples1mg31 kit(96 Wells)100 extractions96 wells (1 kit)5 x 10A5 cells/vial96 samples5 Modulators

Related Pathways

paperclip

#30247945   2018/10/05 To Up

Dacomitinib: an investigational drug for the treatment of glioblastoma.

Standard treatment of newly diagnosed glioblastoma (GB) is surgery with radiotherapy and temozolomide, but tumors will recur with a median overall survival of only 15 months. It seems imperative to explore new possibilities of treatment based on targetable alterations known to be present in GB. Among others, Epidermal Growth Factor Receptor or EGFR (HER1) mutations or amplifications are the most prevalent alterations in GB. In fact, around 40% of GB cases show amplification of EGFR gene, and half of these patients carry the EGFRvIII mutation, a deletion that generates a continuous activation of the tyrosine kinase domain of the receptor. Areas covered: We review the current knowledge about Dacomitinib, an oral, irreversible, second-generation, pan-HER tyrosine kinase inhibitor, in the treatment of glioblastoma. Dacomitinib has noteworthy antiglioma activity in preclinical models and has been tested in one phase II trial in patients with recurrent GB with EGFR amplification. Expert opinion: Despite the poor global results of Dacomitinib in recurrent GB shown in a phase II trial, some patients had a significant benefit. Therefore, it is necessary to improve the knowledge about the mechanisms of failure or resistance to EGFR inhibitors in GB.
Juan Manuel Sepúlveda, Pilar Sánchez-Gómez, María Ángeles Vaz Salgado, Ricardo Gargini, Carmen Balañá

1852 related Products with: Dacomitinib: an investigational drug for the treatment of glioblastoma.

0.1ml (1mg/ml)100.00 ul100μg50 assays0.2 mg100ug0.1 ml

Related Pathways

paperclip

#29620166   2018/03/27 To Up

Antitumour effects and mechanisms of action of the panHER inhibitor, dacomitinib, alone and in combination with the STAT3 inhibitor, S3I-201, in human sarcoma cell lines.

The 5-year survival rate for metastatic sarcoma is 16%. Although the phosphorylated human epidermal growth factor receptor (pEGFR/HER1) has been shown to be an independent predictor of overall survival in patients with sarcoma, we have previously demonstrated that sarcoma cell lines exhibit resistance, despite gefitinib blocking p-EGFR and signal transducers in EGFR downstream pathways. Gefitinib failed to decrease the ratio of phosphorylated (p-)signal transducer and activator of transcription (STAT3)/p-STAT1, suggesting that relative STAT3 abundance and activation may be involved in drug resistance. In this study, we used the panHER inhibitor, dacomitinib, to further block HER2-dependent activation, applying multiple methods, such as proliferation assay, clonogenic survival assay, anti-anoikis assay and western blot analysis. Although dacomitinib inhibited EGFR, HER2, AKT and Erk activation more effectively than gefitinib, it still only exerted minimal anti-proliferative effects on sarcoma cell lines due to the STAT3 escape pathway. However, the addition of the STAT3 inhibitor, S3I-201, to dacomitinib achieved a significant enhancement in growth inhibition, by perturbing p-STAT3/p-STAT1. Using a panel of sarcoma cell lines with different histological types, we identified that the addition of the STAT3 inhibitor enhanced the growth inhibitory effects of the panHER inhibitor, dacomitinib, on sarcoma cells. Our findings may have clinical implications on overcoming the resistance caused by the STAT3 escape pathway and optimising EGFR/panHER-targeted therapy in sarcoma.
Xiaochun Wang, David Goldstein, Philip J Crowe, Jia-Lin Yang

2595 related Products with: Antitumour effects and mechanisms of action of the panHER inhibitor, dacomitinib, alone and in combination with the STAT3 inhibitor, S3I-201, in human sarcoma cell lines.

5 mg5mg1 mg5mg5mg5mg10mg100 5mg5mg5mg5mg

Related Pathways