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Investigation of EGFR/pi3k/Akt signaling pathway in seminomas
F Guerra1, S Quintana2, S Giustina2
1Department of Clinical Biochemistry, Clinical Hospital (UBA), C.A.B.A., INFIBIOC , Córdoba, Argentina.
Abstract:
Activation of the receptor for epidermal growth factor (EGFR) in some testicular tumors activates several signaling pathways. Some components of these pathways are phosphorylated or mutated in testicular germ tumors (TCGT), including EGFR, Kirstein ras oncogen (KRAS) and cell surface protein of the germ cell (KIT). The latter two activate RAF ⁄MEK⁄ERK and PI3 K⁄AKT, and interconnect with the EGFR/pI3 k/Akt pathway. We investigated the expression of EGFR/pI3 k/Akt pathway proteins in seminomas and in their precursor lesion, germinal cell neoplasia in situ (GCNIS) and related genetic mutations. We used immunohistochemistry for pEGFR, pI3 k and pAkt expression with a scoring system for 46 seminoma surgical specimens: 36 classical and 10 GCNIS. In 17 samples, the mutations of EGFR (exons 19 - 21), KIT (exons 11, 17) and KRAS (exons 2, 3) were investigated using qPCR and sequencing. Of the 36 seminomas studied, 22 (61%) expressed pEGFR. Ten samples exhibited high scores for pEGFR, pI3 k and pAkt. In 5 of 17 cases (33%) some mutation was exhibited in the exons studied: 21 of EGFR (2), 17 of EGFR (1), 3 of KRAS (1) and 11 of KIT (1). Six cases exhibited nuclear translocation of EGFR; of these, four exhibited mutations of EGFR, KRAS and KIT. Eight of ten of the GCNIS expressed a high pEGFR score (80%). In 2 of 6 cases (33%), mutation was detected in exon 21 of EGFR and one smear showed EGFR translocation to the nucleus. The translocation represents a subpopulation with worse prognosis for TCGT. The EGFR/pI3 k/Akt signaling pathway is linked to TDRG1, which regulates chemosensitivity to cisplatin; this is a mechanism of resistance to treatment. TDRG1 and the EGFR/pI3 k/pAkt pathway could be therapeutic targets for seminomas resistant to cisplatin.
Insights
The epidermal growth factor receptor (EGFR) pathway is active in testicular germ cell tumors (TCGT). Targeting this pathway and TDRG1 may overcome cisplatin resistance in seminomas.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Activation of the epidermal growth factor receptor (EGFR) pathway is implicated in various cancers, including testicular germ cell tumors (TCGT).
- Key signaling molecules within this pathway, such as EGFR, KRAS, and KIT, can be mutated or phosphorylated in TCGT, influencing tumor progression.
- The PI3K/AKT pathway is a critical downstream effector of EGFR, KRAS, and KIT signaling, playing a role in cell survival and proliferation.
Purpose of the Study:
- To investigate the expression of EGFR/PI3K/Akt pathway proteins in seminomas and their precursor lesions (GCNIS).
- To identify genetic mutations in EGFR, KRAS, and KIT within these tumors.
- To explore the potential of the EGFR/PI3K/Akt pathway and TDRG1 as therapeutic targets for cisplatin-resistant seminomas.
Main Methods:
- Immunohistochemistry was used to assess the expression of phosphorylated EGFR (pEGFR), PI3K (pPI3K), and Akt (pAkt) in 46 seminoma and GCNIS specimens.
- Quantitative PCR (qPCR) and sequencing were employed to detect mutations in EGFR, KIT, and KRAS genes.
- Nuclear translocation of EGFR was also evaluated as a potential prognostic marker.
Main Results:
- Over 60% of seminomas expressed pEGFR, with a significant subset showing high co-expression of pEGFR, pPI3K, and pAkt.
- Mutations in EGFR, KRAS, and KIT were identified in 33% of the analyzed samples.
- EGFR nuclear translocation was observed in a subset of tumors, associated with mutations and potentially indicating a worse prognosis. GCNIS also showed high pEGFR expression.
Conclusions:
- The EGFR/PI3K/Akt signaling pathway is frequently activated in seminomas and GCNIS, suggesting its role in tumorigenesis.
- The presence of mutations and nuclear translocation of EGFR highlights its significance in TCGT.
- The link between this pathway, TDRG1, and cisplatin resistance suggests that targeting EGFR/PI3K/Akt and TDRG1 could be a viable strategy for treating refractory seminomas.
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