Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Treatment of Metastatic Non-Small Cell Lung Cancer, with a Focus on Afatinib

Abdallah, Sami Morin-Ben; Hirsh, Vera

doi:10.3389/fonc.2017.00097

Cited by 13 publications

(9 citation statements)

References 54 publications

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“…The first clinically approved ERBB1/2/4 inhibitor was lapatinib, and was approved for the treatment of breast cancer in combination with capecitabine [ 11 ]. In addition to known activating truncation mutants of ERBB1, primarily found in glioblastoma patients, researchers subsequently identified mutable amino acids in full-length ERBB1 which resulted in the mutant enzyme having a significantly higher basal specific activity [ 12 – 15 ]. Mutant full-length ERBB1 is found in ~10-15% of NSCLC patients, generally in those individuals who have not previously been smokers [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

HDAC inhibitors enhance neratinib activity and when combined enhance the actions of an anti-PD-1 immunomodulatory antibody in vivo

et al. 2017

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Patients whose NSCLC tumors become afatinib resistant presently have few effective therapeutic options to extend their survival. Afatinib resistant NSCLC cells were sensitive to clinically relevant concentrations of the irreversible pan-HER inhibitor neratinib, but not by the first generation ERBB1/2/4 inhibitor lapatinib. In multiple afatinib resistant NSCLC clones, HDAC inhibitors reduced the expression of ERBB1/3/4, but activated c-SRC, which resulted in higher total levels of ERBB1/3 phosphorylation. Neratinib also rapidly reduced the expression of ERBB1/2/3/4, c-MET and of mutant K-/N-RAS; K-RAS co-localized with phosphorylated ATG13 and with cathepsin B in vesicles. Combined exposure of cells to [neratinib + HDAC inhibitors] caused inactivation of mTORC1 and mTORC2, enhanced autophagosome and subsequently autolysosome formation, and caused an additive to greater than additive induction of cell death. Knock down of Beclin1 or ATG5 prevented HDAC inhibitors or neratinib from reducing ERBB1/3/4 and K-/N-RAS expression and reduced [neratinib + HDAC inhibitor] lethality. Neratinib and HDAC inhibitors reduced the expression of multiple HDAC proteins via autophagy that was causal in the reduced expression of PD-L1, PD-L2 and ornithine decarboxylase, and increased expression of Class I MHCA. In vivo, neratinib and HDAC inhibitors interacted to suppress the growth of 4T1 mammary tumors, an effect that was enhanced by an anti-PD-1 antibody. Our data support the premises that neratinib lethality can be enhanced by HDAC inhibitors, that neratinib may be a useful therapeutic tool in afatinib resistant NSCLC, and that [neratinib + HDAC inhibitor] exposure facilitates anti-tumor immune responses.

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Section: Introductionmentioning

confidence: 99%

HDAC inhibitors enhance neratinib activity and when combined enhance the actions of an anti-PD-1 immunomodulatory antibody in vivo

et al. 2017

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“…Several molecular mechanisms underlying the anti-cancer effect of these fatty acids have been proposed. These include the inhibition of cell proliferation and promotion of apoptosis through the tumour suppressor (Hippo) pathway [13]; suppression of pro-inflammatory molecules, prostaglandin PGE 2 , an eicosanoid derived from arachidonic acid (AA) through the COX-2 pathway [43, 44]; promoting cell death via altering the mitochondrial membrane potential [19] and EGFR complex, as well as associated intracellular signalling pathways involving ERK 1/ 2, and mechanistic target rapamycin (mTOR) [45]. Furthermore, EPA and DHA have been reported to downregulate anti-apoptotic proteins and lead to the activation of caspase pathways [46–49].…”

Section: Discussionmentioning

confidence: 99%

Krill oil extract suppresses the proliferation of colorectal cancer cells through activation of caspase 3/9

et al. 2019

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Background Currently available treatments for colorectal cancer (CRC) associate with numerous side-effects that reduce patients’ quality of life. The effective nutraceuticals with high anti-proliferative efficacy and low side-effects are desirable. Our previous study has reported that free fatty acids extract (FFAE) of krill oil induced apoptosis of CRC cells, possibly associated with changes in mitochondrial membrane potential (MMP). The aims of this study were to compare the anti-proliferative efficacy of FFAE from krill oil on CRC cells with commonly used chemotherapeutic drug, Oxaliplatin, and to investigate the molecular mechanisms underlying the anti-proliferative effects of krill oil with a focus on intrinsic mitochondrial death pathway. Methods Three human CRC cell lines, including DLD-1, HT-29 and LIM-2405, and one mouse CRC cell line, CT-26, were treated with FFAE of KO and the bioactive components of krill oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for 24 h and 48 h. Similarly, these cell lines were treated with Oxaliplatin, a commonly used drug for CRC treatment, for 24 h. The effects of FFAE of KO, EPA, DHA and Oxaliplatin on cell proliferation, mitochondrial membrane potential and reactive oxygen species (ROS) were determined via WST-1, JC-10, and ROS assays respectively. The expression of caspase-3, caspase-9 and DNA damage following treatments of FFAE of KO was investigated via western blotting and immunohistochemistry. Results The FFAE of KO, EPA and DHA significantly inhibited cell proliferation and increased formation of ROS in all four cell lines ( P < 0.01). A small dose of FFAE from KO ranged from 0.06 μL/100 μL to 0.12 μL/100 μL containing low concentrations of EPA (0.13–0.52 μM) and DHA (0.06–0.26 μM) achieved similar anti-proliferative effect as Oxaliplatin ( P > 0.05). Treatments with the FFAE of KO, EPA and DHA (2:1 ratio) resulted in a significant increase in the mitochondrial membrane potential ( P < 0.001). Furthermore, the expression of active forms of caspase-3 and caspase-9 was significantly increased following the treatment of FFAE of KO. Conclusions The present study has demonstrated that the anti-proliferative effects of krill oil on CRC cells are comparable with that of Oxaliplatin, and its anti-proliferative property is associated with the activation of caspase 3/9 in the CRC cells.

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“…Long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA), eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), commonly found in fish and other seafoods, have shown beneficial effects on several types of cancer including CRC [ 9 ]. The positive impacts of LC n-3 PUFA on CRC include inhibiting cell proliferation [ 10 ], metastasis and growth [ 11 ]. In addition, they improve patients’ immune function and reduce the toxicity and side-effects of chemotherapy [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Krill oil extract inhibits the migration of human colorectal cancer cells and down-regulates EGFR signalling and PD-L1 expression

Jayathilake

Veale

Luwor

et al. 2020

BMC Complement Med Ther

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Background The currently available treatments for colorectal cancer (CRC) are often associated with serious side-effects. Therefore, the development of a novel nutraceutical agent may provide an alternative complementary therapy for CRC. Overexpression of the epidermal growth factor receptor (EGFR) associates with a range of cancers while downregulation of EGFR signalling can inhibit cancer growth. Our previous studies have shown that the free fatty acid extract (FFAE) of krill oil exhibits anti-proliferative and pro-apoptotic properties. This study determines the effects of krill oil extract on the migration of human CRC cells, and its potential role in modulating EGFR signalling pathway and the expression of programmed death ligand 1 (PD-L1). Methods Human CRC cells, DLD-1 and HT-29 were treated with FFAE of KO at 0.03 and 0.12 μL/100 μL for 8 or 24 h. Cell migration was determined by Boyden chamber migration assay. The expression of EGFR, phosphorylated EGFR (pEGFR), protein kinase B (AKT), phosphorylated AKT (pAKT), extracellular signal regulated kinase (ERK1/2), phosphorylated ERK1/2 (pERK1/2) as well as PD-L1 were assessed by western blotting and immunohistochemistry. Results The FFAE of krill oil significantly inhibited cell migration compared to ethanol-treated (vehicle control) cells (P < 0.01 to P < 0.001). At the molecular level, krill oil extract reduced the expression of EGFR, pEGFR (P < 0.001 for both) and their downstream signalling, pERK1/2 and pAKT (P < 0.01 to P < 0.001) without altering total ERK 1/2 and AKT levels. In addition, the expression of PD-L1 was reduced by 67 to 72% (P < 0.001) following the treatment with krill oil extract. Conclusion This study has demonstrated that krill oil may be a potential therapeutic/adjunctive agent for CRC attributed to its anti-migratory effects.. The potential anti-cancer properties of krill oil are likely to be associated with the downregulation of EGFR, pEGFR and their downstream pERK/ERK1/2 and pAKT/AKT signalling pathways along with the downregulation of PD-L1.

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Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Treatment of Metastatic Non-Small Cell Lung Cancer, with a Focus on Afatinib

Cited by 13 publications

References 54 publications

HDAC inhibitors enhance neratinib activity and when combined enhance the actions of an anti-PD-1 immunomodulatory antibody in vivo

HDAC inhibitors enhance neratinib activity and when combined enhance the actions of an anti-PD-1 immunomodulatory antibody in vivo

Krill oil extract suppresses the proliferation of colorectal cancer cells through activation of caspase 3/9

Krill oil extract inhibits the migration of human colorectal cancer cells and down-regulates EGFR signalling and PD-L1 expression

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