Afatinib radiosensitizes head and neck squamous cell carcinoma cells by targeting cancer stem cells

Macha, Muzafar A.; Rachagani, Satyanarayana; Qazi, Asif Khurshid; Jahan, Rahat; Gupta, Suprit; Patel, Anery; Seshacharyulu, Parthasarathy; Lin, Chi; Li, Sicong; Wang, Shuo; Verma, Vivek; Kishida, Shosei; Kishida, Michiko; Nakamura, Norifumi; Kibe, Toshiro; Lydiatt, William M.; Smith, Russell B.; Ganti, Apar Kishor; Jones, Dwight T.; Batra, Surinder K.; Jain, Maneesh

doi:10.18632/oncotarget.15468

Cited by 41 publications

(36 citation statements)

References 46 publications

(88 reference statements)

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“…Afatinib, by inhibiting the tyrosine kinase activity of EGFR, leads to the inhibition of the PI3K/Akt and RAS/Raf/ERK1/2 pro-survival pathways in both cell lines ( 51 ). By these means, afatinib also establishes a G 0 /G 1 cell cycle arrest, as demonstrated in previous studies in HNSCC ( 38 , 52 ). We also observed a dose-dependent cell-cycle arrest in the G 0 /G 1 phase after 24 h of afatinib exposure.…”

Section: Discussionsupporting

confidence: 80%

“…Similar, an in vivo study highlighted that afatinib combined with gemcitabine had more significant antitumor effect than each drug used alone in a nasopharyngeal xenograft model ( 42 ). More recently, a study using both in vitro and in vivo models showed the interest of afatinib as a radiosensitizer in HNSCC cells by targeting cancer stem cells ( 38 ). Recently, it was also shown that afatinib maintained its cytotoxicity in cetuximab-resistant HNSCC cell lines ( 50 ).…”

Section: Discussionmentioning

confidence: 99%

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Appropriate Sequence for Afatinib and Cisplatin Combination Improves Anticancer Activity in Head and Neck Squamous Cell Carcinoma

et al. 2018

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Despite a better understanding in head and neck tumors pathogenesis as well as improvements in radiotherapy and surgery, locally advanced head and neck squamous cell carcinoma (HNSCC) remains of poor prognosis. One promising target is the epidermal growth factor receptor (EGFR), which is overexpressed in the majority of HNSCC and is associated to tumor progression and resistance to treatment. However, in several clinical trials, the combination of EGFR inhibitors with chemotherapy and/or radiotherapy generates moderate results. In this study, we investigated the anti-tumor activity of afatinib, an irreversible pan-EGFR inhibitor, combined to cisplatin in different schedules of exposure. For that, we used two human EGFR wild-type HNSCC cell lines and we evaluated the cytotoxicity of the two drugs combined in different sequences. The efficiency of each strategy was assessed by evaluating the effects on cell cycle distribution, DNA damage, cell death and downstream pathways of ErbB family receptors. We demonstrated that cisplatin treatment followed by afatinib exposure displayed more cytotoxic effects than the opposite timing or than simultaneous association. This higher anticancer activity is probably due to afatinib-induced cell cycle arrest, which prevents the repair of cisplatin-induced DNA damage and promotes cell death by various mechanisms including apoptosis. These data suggest the importance of an appropriate timing administration between an EGFR inhibitor and a conventional chemotherapy in order to obtain the best clinical benefit for patients with a head and neck cancer.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Appropriate Sequence for Afatinib and Cisplatin Combination Improves Anticancer Activity in Head and Neck Squamous Cell Carcinoma

et al. 2018

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“…In this study, Afatinib overcame intrinsic and acquired cetuximab resistance by inducing cell cycle arrest and thus, apoptosis. In preclinical trials, afatinib achieved a sensitization towards radiotherapy in HNSCC and pancreatic cancer cells [114,115].…”

Section: Afatinib (Gilotrif™)mentioning

confidence: 99%

Molecular Targeting Therapy against EGFR Family in Breast Cancer: Progress and Future Potentials

Maennling

Tur

Niebert

et al. 2019

Cancers

154

109

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The epidermal growth factor receptor (EGFR) family contains four transmembrane tyrosine kinases (EGFR1/ErbB1, Her2/ErbB2, Her3/ErbB3 and Her4/ErbB4) and 13 secreted polypeptide ligands. EGFRs are overexpressed in many solid tumors, including breast, pancreas, head-and-neck, prostate, ovarian, renal, colon, and non-small-cell lung cancer. Such overexpression produces strong stimulation of downstream signaling pathways, which induce cell growth, cell differentiation, cell cycle progression, angiogenesis, cell motility and blocking of apoptosis.The high expression and/or functional activation of EGFRs correlates with the pathogenesis and progression of several cancers, which make them attractive targets for both diagnosis and therapy. Several approaches have been developed to target these receptors and/or the EGFR modulated effects in cancer cells. Most approaches include the development of anti-EGFRs antibodies and/or small-molecule EGFR inhibitors. This review presents the state-of-the-art and future prospects of targeting EGFRs to treat breast cancer.

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“…The primary risk factors for oral cancer are betel nut chewing, smoking, alcohol consumption, human papillomavirus infection, and cell inflammation ( 1 , 4 ). Surgery, radiation therapy, and chemotherapeutic drugs are currently the preferred methods of treating oral cancer ( 4 , 5 ). Cisplatin, carboplatin, 5-fluorouracil, paclitaxel and docetaxel are the chemotherapeutic agents currently used to treat patients with oral cancer ( 6 – 9 ); however, they do not significantly improve survival rates.…”

Section: Introductionmentioning

confidence: 99%

Pterostilbene modulates the suppression of multidrug resistance proteinï¿½1 and triggers autophagic and apoptotic mechanisms in cisplatin-resistant human oral cancer CAR cells via AKT signaling

Chang

Chiang³

et al. 2018

Int J Oncol

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Pterostilbene is a natural polyphenolic compound that is primarily found in fruits, such as blueberries and has a similar structure to resveratrol. Pterostilbene exhibits antioxidant, anti-inflammatory and antitumor activity but the effects of pterostilbene on drug-resistant oral cancer cells and its underlying mechanisms of action have not yet been explored. Therefore, the present study was performed to clarify the anticancer effects of pterostilbene on cisplatin-resistant human oral cancer CAR cells. The results demonstrated that CAR cells exhibited marked shrinkage, cell membrane breakage and autophagic vacuole formation following treatment with pterostilbene. Pterostilbene also effectively inhibited cell viability and suppressed cell confluence in a time- and concentration-dependent manner. Probing with acridine orange, monodansylcadaverine and LysoTracker Red demonstrated that the number of acidic vesicular organelles was increased, indicating increased autophagy. Furthermore, Heochst 33342 staining determined that DNA condensation, a characteristic of apoptosis, was enhanced following treatment with pterostilbene. Furthermore, pterostilbene upregulated mRNA levels of LC3-II and Atg12, as well as the expression of Atgs/Beclin-1/LC3-associated signaling, suggesting that it enhances autophagy. The autophagy inhibitors 3-methyladenine and chloroquine were used to confirm that pterostilbene induces autophagy. It was also determined that pterostilbene triggered caspase-dependent apoptosis by directly testing DNA breakage and using the pan-caspase inhibitor carbobenzoxyvalyl-alanyl-aspartyl fluoromethyl ketone. The results demonstrated that pterostilbene mediates the apoptosis of CAR cells via the intrinsic apoptotic cascade. In addition, pterostilbene inhibited MDR1 expression and the phosphorylation of AKT on the Ser473 site in CAR cells. Therefore, pterostilbene may elicit an oral anticancer response in drug-resistant cells and may be used as a chemotherapeutic adjuvant to treat patients with oral cancer.

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Afatinib radiosensitizes head and neck squamous cell carcinoma cells by targeting cancer stem cells

Cited by 41 publications

References 46 publications

Appropriate Sequence for Afatinib and Cisplatin Combination Improves Anticancer Activity in Head and Neck Squamous Cell Carcinoma

Appropriate Sequence for Afatinib and Cisplatin Combination Improves Anticancer Activity in Head and Neck Squamous Cell Carcinoma

Molecular Targeting Therapy against EGFR Family in Breast Cancer: Progress and Future Potentials

Pterostilbene modulates the suppression of multidrug resistance proteinï¿½1 and triggers autophagic and apoptotic mechanisms in cisplatin-resistant human oral cancer CAR cells via AKT signaling

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