EGFR Alterations Influence the Cetuximab Treatment Response and c-MET Tyrosine-Kinase Inhibitor Sensitivity in Experimental Head and Neck Squamous Cell Carcinomas

Abstract

Background: Anti-EGFR antibody therapy is still one of the clinical choices in head and neck squamous cell carcinoma (HNSCC) patients, but the emergence of cetuximab resistance questioned its effectiveness and reduced its applicability. Although several possible reasons of resistance against the antibody treatment and alternative therapeutic proposals have been described (EGFR alterations, activation of other signaling pathways), there is no method to predict the effectiveness of anti-EGFR antibody treatments and to suggest novel therapeutics. Our study investigated the effect of EGFR R521K alteration on efficiency of cetuximab therapy of HNSCC cell lines and tried to find alternative therapeutic approaches against the resistant cells.Methods: After genetic characterization of HNSCC cells, we chose one wild type and one R521K+ cell line for in vitro proliferation and apoptosis tests, and in vivo animal models using different therapeutic agents.Results: Although the cetuximab treatment affected EGFR signalization in both cells, it did not alter in vitro cell proliferation or apoptosis. In vivo cetuximab therapy was also ineffective on R521K harboring tumor xenografts, while blocked the tumor growth of EGFR-wild type xenografts. Interestingly, the cetuximab-resistant R521K tumors were successfully treated with c-MET tyrosine kinase inhibitor SU11274.Conclusion: Our results suggest that HNSCC cell line expressing the R521K mutant form of EGFR does not respond well to cetuximab treatment in vitro or in vivo, but hopefully might be targeted by c-MET tyrosine kinase inhibitor treatment.

Genetic polymorphisms associated with the response of head and neck carcinoma to cetuximab

“…El EGFR-K 521 o alelo K, se expresa en más del 40% de los casos de CCECC y se ha reportado que su presencia produce una variante del EGFR que muestra una función disminuida, al presentar una menor afinidad por sus dos principales ligandos endógenos (factor de c recimiento epidémico y el factor a transformador del crecimiento), así como una disminución en su actividad mitogénica. Los mecanismos moleculares que subyacen a estos resultados no están claramente definidos, pero se ha planteado que el intercambio de aminoácidos produce una reducción en la afinidad y estabilidad del c etuximab en el EGFR K 521 (28,30,40).…”

Cetuximab chemotherapy resistance: Insight into the homeostatic evolution of head and neck cancer (Review)

“…In addition to the HER family and the downstream effectors, EGFR blockade in HNSCC results in the activation of several alternative growth factor receptor pathways, such as anaplastic lymphoma kinase (ALK), insulin-like growth factor (IGF)-1 and hepatocyte growth factor (MET), which are members of the RTK family ( 128 ). MET activation modulates several signaling cascades, including PI3K/AKT, JAK/STAT, Ras/MAPK, SRC and Wnt/β-catenin ( 129 ).…”

EGFR Mutations in Head and Neck Squamous Cell Carcinoma

“…The authors suggested this polymorphism could be used as a prognostic predictor of therapeutic resistance, which is discussed in subsequent sections of this review. While most mutations are acquired in response to therapy, one report showed that the presence of a R521K substitution in both in vitro and in vivo HNSCC models rendered tumors resistant to CTX but sensitive to a c-MET TKI (SU11274) [ 31 ]. Interestingly, a discrepancy in EGFR expression between the primary tumor and metastatic brain lesions was observed in a patient under long-term CTX treatment who eventually acquired resistance [ 32 ].…”

“…Two separate studies examined the presence of a single nucleotide polymorphism (SNP) EGFR-K 521 in different HNSCC clinical cohorts and found that while the SNP was not associated with the risk of cancer, it correlated with response to CTX treatment [ 30 , 80 ]. In vitro studies showed that HNSCC cells with a R521K substitution in the ECD did not respond to CTX treatment; cell proliferation and apoptosis remained unimpacted in both in vitro and in vivo models indicative of intrinsic resistance to CTX [ 31 ].…”