Synergistic Growth Inhibition by Afatinib and Trametinib in Preclinical Oral Squamous Cell Carcinoma Models.

Yee PS; Zainal NS; Gan CP; Lee BKB; Mun KS; Abraham MT; Ismail SM; Abdul Rahman ZA; Patel V; Cheong SC

doi:10.1007/s11523-019-00626-8

Synergistic Growth Inhibition by Afatinib and Trametinib in Preclinical Oral Squamous Cell Carcinoma Models.

Affiliations

1. Head and Neck Cancer Research Team, Cancer Research Malaysia, No. 1, Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia.
Authors
Yee PS^{1,

4}
Zainal NS^{1,

4}
Gan CP¹
Lee BKB^{1,

4}
Patel V¹
Cheong SC^{1,

4}
(6 authors)
2. Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Authors
Mun KS²
(1 author)
3. Department of Oral and Maxillofacial Surgery, Tengku Ampuan Rahimah Hospital, Klang, Malaysia.
Authors
Abraham MT³
(1 author)
4. Department of Oral and Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
Authors
Yee PS^{1,

4}
Zainal NS^{1,

4}
Lee BKB^{1,

4}
Ismail SM⁴
Abdul Rahman ZA⁴
Cheong SC^{1,

4}
(6 authors)

ORCIDs linked to this article

Targeted Oncology, 01 Apr 2019, 14(2):223-235
https://doi.org/10.1007/s11523-019-00626-8 PMID: 30806895

Abstract

Background

Given that aberrant activation of epidermal growth factor receptor family receptors (ErbB) is a common event in oral squamous cell carcinoma, and that high expression of these receptor proteins is often associated with poor prognosis, this rationalizes the approach of targeting ErbB signaling pathways to improve the survival of patients with oral squamous cell carcinoma. However, monotherapy with the ErbB blocker afatinib has shown limited survival benefits.

Objectives

This study was performed to identify mechanisms of afatinib resistance and to explore potential afatinib-based combination treatments with other targeted inhibitors in oral squamous cell carcinoma.

Methods

We determined the anti-proliferative effects of afatinib on a panel of oral squamous cell carcinoma cell lines using a crystal violet-growth inhibition assay, click-iT 5-ethynyl-2'-deoxyuridine staining, and cell-cycle analysis. Biochemical assays were performed to study the underlying mechanism of drug treatment as a single agent or in combination with the MEK inhibitor trametinib. We further evaluated and compared the anti-tumor effects of single agent and combined treatment by using oral squamous cell carcinoma xenograft models.

Results

In this study, we showed that afatinib inhibited oral squamous cell carcinoma cell proliferation via cell-cycle arrest at the G₀/G₁ phase, and inhibited tumor growth in xenograft mouse models. Interestingly, we demonstrated reactivation of the mitogen-activated protein kinase (ERK1/2) pathway in vitro, which possibly reduced the effects of ErbB inhibition. Concomitant treatment of oral squamous cell carcinoma cells with afatinib and trametinib synergized the anti-tumor effects in oral squamous cell carcinoma-bearing mouse models.

Conclusions

Our findings provide insight into the molecular mechanism of resistance to afatinib and support further clinical evaluation into the combination of afatinib and MEK inhibition in the treatment of oral squamous cell carcinoma.

Full text links

Read article at publisher's site: https://doi.org/10.1007/s11523-019-00626-8

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Funders who supported this work.

Ministry of Higher Education, Malaysia (1)

Grant ID: UM.C/625/1/HIR/MOHE/DENT-03
1 publication

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Synergistic Growth Inhibition by Afatinib and Trametinib in Preclinical Oral Squamous Cell Carcinoma Models.

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