scholarly journals Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA

Science ◽  
2013 ◽  
Vol 343 (6166) ◽  
pp. 72-76 ◽  
Author(s):  
David A. Nathanson ◽  
Beatrice Gini ◽  
Jack Mottahedeh ◽  
Koppany Visnyei ◽  
Tomoyuki Koga ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Therapy Resistance ◽  
Cancer Drug ◽  
Clinical Samples ◽  
Extrachromosomal Dna ◽  
Dynamic Regulation ◽  
Cancer Drug Resistance ◽  
Egfr Expression ◽  
Mutant Egfr

Intratumoral heterogeneity contributes to cancer drug resistance, but the underlying mechanisms are not understood. Single-cell analyses of patient-derived models and clinical samples from glioblastoma patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate that tumor cells reversibly up-regulate or suppress mutant EGFR expression, conferring distinct cellular phenotypes to reach an optimal equilibrium for growth. Resistance to EGFR TKIs is shown to occur by elimination of mutant EGFR from extrachromosomal DNA. After drug withdrawal, reemergence of clonal EGFR mutations on extrachromosomal DNA follows. These results indicate a highly specific, dynamic, and adaptive route by which cancers can evade therapies that target oncogenes maintained on extrachromosomal DNA.

scholarly journals Mechanisms of CDK4/6 Inhibitor Resistance in Luminal Breast Cancer

2020 ◽  
Vol 11 ◽  
Author(s):  
Zhen Li ◽  
Wei Zou ◽  
Ji Zhang ◽  
Yunjiao Zhang ◽  
Qi Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Cancer Drug ◽  
Luminal Breast Cancer ◽  
Cancer Drug Resistance ◽  
Estrogen Receptor Positive ◽  
Underlying Mechanisms ◽  
Inhibitor Resistance ◽  
New Generation

As a new-generation CDK inhibitor, a CDK4/6 inhibitor combined with endocrine therapy has been successful in the treatment of advanced estrogen receptor–positive (ER+) breast cancer. Although there has been overall progress in the treatment of cancer, drug resistance is an emerging cause for breast cancer–related death. Overcoming CDK4/6 resistance is an urgent problem. Overactivation of the cyclin-CDK-Rb axis related to uncontrolled cell proliferation is the main cause of CDK4/6 inhibitor resistance; however, the underlying mechanisms need to be clarified further. We review various resistance mechanisms of CDK4/6 inhibitors in luminal breast cancer. The cell signaling pathways involved in therapy resistance are divided into two groups: upstream response mechanisms and downstream bypass mechanisms. Finally, we discuss possible strategies to overcome CDK4/6 inhibitor resistance and identify novel resistance targets for future clinical application.

Epidermal growth factor receptor (EGFR) inhibition in triple-negative breast cancer (BrCa)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14071-14071 ◽  
Author(s):  
B. Corkery ◽  
N. O’Donovan ◽  
M. Clynes ◽  
J. Crown
Keyword(s):  
Cell Lines ◽  
Hormone Receptors ◽  
Kinase Inhibitors ◽  
Triple Negative ◽  
Growth Factor Receptor ◽  
Significant Inhibition ◽  
Inhibition Of Proliferation ◽  
Egfr Inhibition ◽  
Negative Cell ◽  
Egfr Expression

14071 Background: Triple-negative BrCa lacks expression of hormone receptors and HER-2 but does express EGFR. It is associated with early relapse and poor survival. There is no targeted therapy for triple-negative BrCa. We are studying the potential role of EGFR inhibition. Methods: EGFR expression was examined in triple-negative BrCa cell lines, (BT20, HCC1937, and MDA-MB-231) by western blot. IC50 assays were determined for three EGFR inhibitors, gefitinib (G) and erlotinib (T), which are small-molecule tyrosine kinase inhibitors, and cetuximab (E) which is a monoclonal antibody against EGFR, and chemotherapy (CRx) drugs docetaxel (D) and carboplatin (P)), using the acid phosphatase assay. The controls were HER2+ BrCa cell lines, BT474 and SKBR3 which express low levels of EGFR. Results: The three triple-negative cell lines over-express EGFR. IC50 values for G and T were significantly higher in the triple-negative than in the HER2+ cell lines. E did not cause significant inhibition in any cell line (max inhibition 20% at 100 μg/ml E). IC50 values for G were lower than for T in the triple-negative cell lines (IC50s for HCC1937: G - 8.4 ± 1.5 μM; T - 26.2 ± 9.3 μM). Combined EGFR inhibition with CRx was tested in HCC1937 cells. G combined with P or with D for 5 days showed an additive effect on inhibition of proliferation ( Table 1 ). Alternate scheduling of the drugs did not significantly influence response. Conclusions: Our results suggest that triple-negative BrCa cells over-express EGFR but are not as sensitive to EGFR inhibition as HER2+ BrCa cells. However, EGFR inhibition may enhance response to CRx in triple-negative BrCa. [Table: see text] No significant financial relationships to disclose.

scholarly journals In-frame deletion in the EGF receptor alters kinase inhibition by gefitinib

2006 ◽  
Vol 397 (3) ◽  
pp. 537-543 ◽  
Author(s):  
Kazuko Sakai ◽  
Hideyuki Yokote ◽  
Kimiko Murakami-Murofushi ◽  
Tomohide Tamura ◽  
Nagahiro Saijo ◽  
...  
Keyword(s):  
Kinetic Parameters ◽  
Deletion Mutant ◽  
Kinase Inhibitors ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Kinetic Studies ◽  
Wild Type ◽  
Lung Cancers ◽  
The Difference ◽  
Mutant Egfr

The existence of an in-frame deletion mutant correlates with the sensitivity of lung cancers to EGFR (epidermal growth factor receptor)-targeted tyrosine kinase inhibitors. We reported previously that the in-frame 15-bp deletional mutation (delE746–A750 type deletion) was constitutively active in cells. Kinetic parameters are important for characterizing an enzyme; however, it remains unclear whether the kinetic parameters of deletion mutant EGFR are similar to those of wild-type EGFR. We analysed autophosphorylation in response to ATP and inhibition of gefitinib for deletion mutant EGFR and wild-type EGFR. Kinetic studies, examining autophosphorylation, were carried out using EGFR fractions extracted from 293-pΔ15 and 293-pEGFR cells transfected with deletion mutant EGFR and wild-type EGFR respectively. We demonstrated the difference in activities between unstimulated wild-type (Km for ATP=4.0±0.3 μM) and mutant EGFR (Km for ATP=2.5±0.2 μM). There was no difference in Km values between EGF-stimulated wild-type EGFR (Km for ATP=1.9±0.1 μM) and deletion mutant EGFR (Km for ATP=2.2±0.2 μM). These results suggest that mutant EGFR is active without ligand stimulation. The Ki value for gefitinib of the deletion mutant EGFR was much lower than that of wild-type EGFR. These results suggest that the deletion mutant EGFR has a higher affinity for gefitinib than wild-type EGFR.

scholarly journals Targeting the DNA Damage Response to Overcome Cancer Drug Resistance in Glioblastoma

2020 ◽  
Vol 21 (14) ◽  
pp. 4910 ◽  
Author(s):  
Alessandra Ferri ◽  
Venturina Stagni ◽  
Daniela Barilà
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Kinase Inhibitors ◽  
Cancer Drug ◽  
Special Focus ◽  
Dna Repair Mechanisms ◽  
Cancer Drug Resistance ◽  
Damage Response ◽  
Repair Mechanisms ◽  
Future Therapy

Glioblastoma multiforme (GBM) is a severe brain tumor whose ability to mutate and adapt to therapies is at the base for the extremely poor survival rate of patients. Despite multiple efforts to develop alternative forms of treatment, advances have been disappointing and GBM remains an arduous tumor to treat. One of the leading causes for its strong resistance is the innate upregulation of DNA repair mechanisms. Since standard therapy consists of a combinatory use of ionizing radiation and alkylating drugs, which both damage DNA, targeting the DNA damage response (DDR) is proving to be a beneficial strategy to sensitize tumor cells to treatment. In this review, we will discuss how recent progress in the availability of the DDR kinase inhibitors will be key for future therapy development. Further, we will examine the principal existing DDR inhibitors, with special focus on those currently in use for GBM clinical trials.

scholarly journals Epithelial Transfer of the Tyrosine Kinase Inhibitors Erlotinib, Gefitinib, Afatinib, Crizotinib, Sorafenib, Sunitinib, and Dasatinib: Implications for Clinical Resistance

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3322
Author(s):  
Richard J. Honeywell ◽  
Ietje Kathmann ◽  
Elisa Giovannetti ◽  
Carmelo Tibaldi ◽  
Egbert F. Smit ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Red Blood Cells ◽  
Tyrosine Kinase Inhibitors ◽  
Blood Cells ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Clinical Samples ◽  
Clinical Resistance ◽  
Colon Cell ◽  
Epidermal Growth

Background: tyrosine kinase inhibitors (TKIs) inhibit phosphorylation of signaling proteins. TKIs often show large variations in the clinic due to poor pharmacology, possibly leading to resistance. We compared gut absorption of inhibitors of epidermal growth factor receptor (erlotinib, gefitinib, and afatinib), ALK-cMET (crizotinib), PDGFR/BCR-Abl (dasatinib), and multikinase inhibitors (sunitinib and sorafenib). In clinical samples, we measured the disposition of each compound within various blood compartments. Methods: we used an optimized CaCo2 gut epithelial model to characterize 20 µM TKI absorption. The apical/basolateral transfer is considered to represent the gut/blood transfer. Drugs were measured using LC-MS/MS. Results: sorafenib and sunitinib showed the highest apical/basolateral transfer (Papp 14.1 and 7.7 × 10−6 cm/s, respectively), followed by dasatinib (3.4), afatinib (1.5), gefitinib (0.38), erlotinib (0.13), and crizotinib (n.d.). However, the net absorptions for dasatinib, afatinib, crizotinib, and erlotinib were highly negative (efflux ratios >5) or neutral/negative, sorafenib (0.86), gefitinib (1.0), and sunitinib (1.6). A high negative absorption may result in resistance because of a poor exposure of tissues to the drug. Accumulation of the TKIs at the end of the transfer period (A->B) was not detectable for erlotinib, very low for afatinib 0.45 pmol/μg protein), followed by gefitinib (0.79), dasatinib (1.1), sorafenib (1.65), and crizotinib (2.11), being highest for sunitinib (11.9). A similar pattern was found for accumulation of these drugs in other colon cell lines, WiDr and HT29. In clinical samples, drugs accumulated consistently in red blood cells; blood to plasma ratios were all >3 (sorafenib) or over 30 for erlotinib. Conclusions: TKIs are consistently poorly absorbed, but accumulation in red blood cells seems to compensate for this.

scholarly journals Cancer drug resistance induced by EMT: novel therapeutic strategies

2021 ◽  
Author(s):  
Javier De Las Rivas ◽  
Anamaria Brozovic ◽  
Sivan Izraely ◽  
Alba Casas-Pais ◽  
Isaac P. Witz ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Epithelial To Mesenchymal Transition ◽  
Therapy Resistance ◽  
Tumour Microenvironment ◽  
Limiting Factors ◽  
Cancer Drug ◽  
Clinical Samples ◽  
Cancer Therapies ◽  
Mesenchymal Transition ◽  
Clinical Benefits

AbstractOver the last decade, important clinical benefits have been achieved in cancer patients by using drug-targeting strategies. Nevertheless, drug resistance is still a major problem in most cancer therapies. Epithelial-mesenchymal plasticity (EMP) and tumour microenvironment have been described as limiting factors for effective treatment in many cancer types. Moreover, epithelial-to-mesenchymal transition (EMT) has also been associated with therapy resistance in many different preclinical models, although limited evidence has been obtained from clinical studies and clinical samples. In this review, we particularly deepen into the mechanisms of which intermediate epithelial/mesenchymal (E/M) states and its interconnection to microenvironment influence therapy resistance. We also describe how the use of bioinformatics and pharmacogenomics will help to figure out the biological impact of the EMT on drug resistance and to develop novel pharmacological approaches in the future.

scholarly journals Molecular mechanisms of the anti-cancer drug, LY2874455, in overcoming the FGFR4 mutation-based resistance

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fariba Dehghanian ◽  
Shahryar Alavi
Keyword(s):  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Substrate Binding ◽  
Growth Factor Receptor ◽  
Binding Pocket ◽  
Cancer Drug ◽  
Inhibition Mechanism ◽  
Wild Type ◽  
Substrate Binding Pocket ◽  
Anti Cancer

AbstractIn recent years, many strategies have been used to overcome the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors (TKIs) resistance caused by different mutations. LY2874455 (or 6LF) is a pan-FGFR inhibitor which is identified as the most efficient TKI for all resistant mutations in FGFRs. Here, we perform a comparative dynamics study of wild type (WT) and the FGFR4 V550L mutant for better understanding of the 6LF inhibition mechanism. Our results confirm that the pan-FGFR inhibitor 6LF can bind efficiently to both WT and V550L FGFR4. Moreover, the communication network analysis indicates that in apo-WT FGFR4, αD–αE loop behaves like a switch between open and close states of the substrate-binding pocket in searching of its ligand. In contrast, V550L mutation induces the active conformation of the FGFR4 substrate-binding pocket through disruption of αD–αE loop and αG helix anti-correlation. Interestingly, 6LF binding causes the rigidity of hinge and αD helix regions, which results in overcoming V550L induced resistance. Collectively, the results of this study would be informative for designing more efficient TKIs for more effective targeting of the FGFR signaling pathway.

scholarly journals NRF2 Enables EGFR Signaling in Melanoma Cells

2021 ◽  
Vol 22 (8) ◽  
pp. 3803
Author(s):  
Julia Katharina Charlotte Kreß ◽  
Christina Jessen ◽  
André Marquardt ◽  
Anita Hufnagel ◽  
Svenja Meierjohann
Keyword(s):  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Head And Neck Carcinoma ◽  
Antioxidant Response ◽  
Therapy Resistance ◽  
Sequencing Data ◽  
Chip Sequencing ◽  
Egfr Expression ◽  
Pathway Activation ◽  
Electrophilic Stress

Receptor tyrosine kinases (RTK) are rarely mutated in cutaneous melanoma, but the expression and activation of several RTK family members are associated with a proinvasive phenotype and therapy resistance. Epidermal growth factor receptor (EGFR) is a member of the RTK family and is only expressed in a subgroup of melanomas with poor prognosis. The insight into regulators of EGFR expression and activation is important for the understanding of the development of this malignant melanoma phenotype. Here, we describe that the transcription factor NRF2, the master regulator of the oxidative and electrophilic stress response, mediates the expression and activation of EGFR in melanoma by elevating the levels of EGFR as well as its ligands EGF and TGFα. ChIP sequencing data show that NRF2 directly binds to the promoter of EGF, which contains a canonical antioxidant response element. Accordingly, EGF is induced by oxidative stress and is also increased in lung adenocarcinoma and head and neck carcinoma with mutationally activated NRF2. In contrast, regulation of EGFR and TGFA occurs by an indirect mechanism, which is enabled by the ability of NRF2 to block the activity of the melanocytic lineage factor MITF in melanoma. MITF effectively suppresses EGFR and TGFA expression and therefore serves as link between NRF2 and EGFR. As EGFR was previously described to stimulate NRF2 activity, the mutual activation of NRF2 and EGFR pathways was investigated. The presence of NRF2 was necessary for full EGFR pathway activation, as NRF2-knockout cells showed reduced AKT activation in response to EGF stimulation compared to controls. Conversely, EGF led to the nuclear localization and activation of NRF2, thereby demonstrating that NRF2 and EGFR are connected in a positive feedback loop in melanoma. In summary, our data show that the EGFR-positive melanoma phenotype is strongly supported by NRF2, thus revealing a novel maintenance mechanism for this clinically challenging melanoma subpopulation.

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