Simultaneous targeting of EGFR, HER2, and HER4 by afatinib overcomes intrinsic and acquired cetuximab resistance in head and neck squamous cell carcinoma cell lines

Abstract

The epidermal growth factor receptor (EGFR, HER1) is a therapeutic target in head and neck squamous cell carcinoma (HNSCC). After initial promising results with EGFR‐targeted therapies such as cetuximab, therapeutic resistance has become a major clinical problem, and new treatment options are therefore necessary. Moreover, the relationship between HER receptors, anti‐EGFR therapies, and the human papillomavirus (HPV) status in HNSCC is not fully understood. In contrast to first‐generation EGFR inhibitors, afatinib irreversibly inhibits multiple HER receptors simultaneously. Therefore, treatment with afatinib might result in a more pronounced therapeutic benefit, even in patients experiencing cetuximab resistance. In this study, the cytotoxic effect of afatinib as single agent and in combination with cisplatin was investigated in cetuximab‐sensitive, intrinsically cetuximab‐resistant, and acquired cetuximab‐resistant HNSCC cell lines with different HPV status under normoxia and hypoxia. Furthermore, the influence of cetuximab resistance, HPV, and hypoxia on the expression of HER receptors was investigated. Our results demonstrated that afatinib was able to establish cytotoxicity in cetuximab‐sensitive, intrinsically cetuximab‐resistant, and acquired cetuximab‐resistant HNSCC cell lines, independent of the HPV status. However, cross‐resistance between cetuximab and afatinib might be possible. Treatment with afatinib caused a G0/G1 cell cycle arrest as well as induction of apoptotic cell death. Additive to antagonistic interactions between afatinib and cisplatin could be observed. Neither cetuximab resistance nor HPV status significantly influenced the expression of HER receptors in HNSCC cell lines. In contrast, the expression of EGFR, HER2, and HER3 was significantly altered under hypoxia. Oxygen deficiency is a common characteristic of HNSCC tumors, and these hypoxic tumor regions often contain cells that are more resistant to treatment. However, we observed that afatinib maintained its cytotoxic effect under hypoxia. In conclusion, our preclinical data support the hypothesis that afatinib might be a promising therapeutic strategy to treat patients with HNSCC experiencing intrinsic or acquired cetuximab resistance.

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

“…Due to the inactivity of the kinase in Her3 and thus to the requirement of a heterodimerization with other ErbB receptors for its activation, blocking the receptor partners leads to the suppression of Her3 activity [111]. This means that TKIs that inhibit other EGFRs indirectly act as Her3 inhibitors as well.…”

“…Afatinib (Gilotrif™) is an irreversible TKI that simultaneously targets EFR, Her2 and Her4 [113]. Due to the inhibition of the interaction partners, afatinib also suppresses the Her3-mediated signaling [111]. De Pauw and colleagues (2018) investigated the synergistic effect of afatinib and cetuximab in cetuximab-sensitive and -resistant head and neck squamous cell carcinoma (HNSCC) cell lines.…”

A Drug Recommendation System (Dr.S) for Cancer Cell Lines

“…For example we see that for Nutlin-3a, our models found TP53 and BAX as strong predictors: Nutlin-3a disrupts the P53 pathway by interfering with the interaction between P53 and MDM2, and BAX is an apoptotic activator which is regulated by P53 [Weinberg, 2007]. Afatinib is a tyrosine kinase inhibitor and is known to interact with EGFR and ERBB2 [De Pauw et al, 2018]. In nearly all of the FI plots (SI Figure 2) we see that elastic net and random forest revealed distinct features as important, which likely relates to the fact that elastic net determines only features that are linearly related to the response variable, while random forest can capture non-linear relationships as well.…”

Современные Аспекты Лечения Плоскоклеточного Рака Головы И шеи

“…Цетуксимаб взаимодействует также с мутантным рецептором EGFRvIII (del27), вызывая интернализацию 50% лигандрецепторных комплексов и на 80% снижая фосфорилирование EGFRvIII. Цетуксимаб ингибирует связывание ERBB1 с эндогенными ростовыми факторами, подавляет клеточную подвижность и образование метастазов, индуцирует апоптоз раковых клеток, а также подавляет образование проангиогенных факторов VEGF и интерлейкина 8 [8,9,10].…”