Growth Factor Receptors and Tyrosine Kinases

Growth factor receptors mitigate their intracellular signal transduction pathway via intracellular tyrosine kinases that modulate cellular functions such as protein synthesis, cell turnover, cell adhesion and migration, among other processes. Several growth factor receptor inhibitors and tyrosine kinase inhibitors (TKIs) have been developed in the last decade. They have entered clinical use, notably in renal cell cancer where agents such as sunitinib, sorafenib, and bevacizumab are showing clinical utility as single agent therapies. In non-small cell lung cancer epidermal growth factor receptor (EGFR) mutation or over-expression predicted for response to Erlotinib, however, screening for mutations appeared to have most benefit among women with non-squamous malignancy. 20 Clinical trials of EGFR antibodies or TKIs had only modest survival benefits in lung cancer. This may well be due to redundancy in the signaling pathways, with several different receptor tyrosine kinase being simultaneously activated such that inhibition of only one may not have a large impact on downstream effects. This has been demonstrated in glioblastoma cell lines and tumor tissue where the activation of multiple receptor tyrosine kinases was shown. In fact, downstream signaling was only affected with the use of combined strategies (i.e., erlotinib, imatinib, and a C-met inhibitor together).31

Another factor in the impact of targeted therapy may be the magnitude of inhibition. While many epithelial malignancies over-express EGFR, the degree of up-regulation may vary. A recent paper correlated lung cancer histopathology with the expression of EGFR.22 Over-expression was more prevalent in squamous cell carcinomas (SCC) than adenocarcinomas (ADC) (71% vs. 48%). Until recently, no trial or case report had explored the application of such agents in penile cancer.3 3 Pagliaro et al. recently described a preliminary experience with EGFR expression and therapy among patients with metastatic penile cancer.34 Thirteen cases were assayed for EGFR expression with tissue from lymph node metastasis in five patients, inguinal or scrotal skin metastasis in two patients, and the primary tumor in six patients. Tumor cells in all cases were positive for EGFR, and 9 were scored as 3+ or strongly positive. All of the patients received one or more EGFR-targeted therapies including erlotinib (one patient), cetuximab (three patients), or cetuximab combined with one or more cytotoxic agents (nine patients). Six patients received a second or third EGFR-targeted therapy. Grade 3 or 4 adverse events were limited to cellulitis, throm-bocytopenia, and tumor hemorrhage (one patient each). Two patients had disease progression during initial treatment with paclitaxel, ifosfamide, and cisplatin (TIP), then had partial responses to TIP plus cetuximab. Two patients had partial responses to cetuximab and cisplatin, also after having disease progression while receiving TIP. A patient with visceral metastases who had extensive prior chemotherapy received cetuximab and cisplatin as salvage treatment and experienced objective tumor regression lasting 3 months. These results indicate that EGFR plays a clinically important role in metastatic penile carcinoma and is a promising target for therapy.

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