Abstract 3137: Oncogenic activation of PI3K and MAPK pathways in 95 aggressive thyroid carcinomas (PDC and ATC). Co-activation prevalence

Abstract

Abstract The MAPK and the PI3K pathways are viewed as therapeutic targets of the future due to their pivotal role in cellular proliferation, growth regulation, survival, adhesion, motility and spreading. While genetic alterations of effectors along the MAPK pathway are early events in thyroid follicular cell carcinogenesis, being some of them (oncogenic BRAF and RAS activation) also involved in tumour dedifferentiation and progression, the genetic alterations of effectors along the PI3K pathway are normally associated with late stage, advanced thyroid cancers. So far only one study has addressed the prevalence of PIK3CA mutations in poorly differentiated thyroid carcinomas (PDC). Because conventional treatment is clearly ineffective among late stage, advanced thyroid cancers in this study we focused on genotyping “druggable” oncogenes encoding effectors of both pathways. Mutations at BRAF, H-, K-, N-RAS and PIK3CA were investigated by PCR-SSCP-direct sequencing in 40 PDC and 55 anaplastic thyroid carcinomas (ATC). Focal changes in the growth pattern or microscopic grade within the primary tumour, recurrences and metastases were separately genotyped (144 samples). Mutational status was correlated with the expression of downstream effectors such as p-ERK and p-AKT. While the overall prevalence of PIK3CA mutations and BRAF mutations in ATC was almost twice that of PDC [PIK3CA: 29% and 20% respectively; BRAF: 22% and 12.5% respectively], the overall prevalence of RAS mutations in PDC resulted considerably higher than in ATC [45% and 36% respectively]. Concurrent BRAF and RAS mutations were present in 2 PDC (5%) and 5 ATC (9%). Concurrent RAS and PIK3CA mutations were found in 4 PDC (10%) and 4 ATC (7%). Concurrent BRAF and PIK3CA mutations or concurrent BRAF + RAS + PIK3CA mutations were only identified among ATC (2 cases, 4%). Activation of AKT was observed in most PDC and ATC harbouring PIK3CA mutations [86% and 90% respectively]. Phospho-p44/42 MAPK, which specifically recognizes the dually phosphorylated and active forms of ERK1 and ERK2 was present in 50% of the PDC and 55.5% of the ATC bearing the BRAFV600E mutation. PDC and ATC with RAS mutations were found to signal preferentially via PI3K. Among the RAS mutated PDC 69% demonstrated activation of AKT and 31% activation of ERK. Among RAS mutated ATC 85% exhibited AKT activation and 46% ERK activation. Co-activation of both pathways (p-AKT and p-ERK) was seen in 2 PDC (12.5%, both cases RAS +) and 5 ATC [38%; 4 cases RAS + plus 1 case RAS + and BRAF +]. Strikingly, all 4 PDC mutated at RAS and PIK3CA had distant metastases at diagnosis and died of disease. These findings may significantly impact on the rationale of future, tailored gene targeted therapies applied to patients with ATC and PDC. Our results suggest that activation of the PI3K pathway is pivotal in disease dedifferentiation and progression which has important implications in PDC and ATC management. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3137.