Inactivating mutations of TP53 and resistence to tyrosine-kinase inhibitors in patients affected with aggressive thyroid cancer

Objectives: Well differentiated thyroid cancers (WDTC) are generally sensitive to first line treatments or eventually to tyrosine kinase inhibitors (TKIs). However, a part of WDTC together with poorly differentiated (PDTC) and anaplastic (ATC) thyroid cancers are particularly aggressive and refractory to all treatments, TKIs included. Since TKIs resistance is proven to be related with the presence of TP53 mutations in other tumours, and TP53 alterations are frequently detected in aggressive thyroid cancer (TC), we aimed to investigate the possible correlation between TP53 mutational status and resistance to TKIs in patients with aggressive TC. Methods: The molecular analysis of TP53 was performed in a cohort of 30 patients bearing aggressive TC (24 WDTC and 6 PDTC/ATC) and treated with TKIs by Sanger sequencing. Results: TP53 mutations were detected in 7/30 (23.3%) tumour tissues (3 WDTC and 4 PDTC/ATC) and fall within exons 5-8 encoding the DNA binding domain of the protein. Three mutations were already reported in TC (p.C135Y, c.626_627delGA, p.Q192X), 4 reported in other solid or haematological malignancies (p.M133R, p.C135F, c.722_724delTCC, p.H214Y) and 1 never reported in any tumour (c.866_867delTC). Interestingly, patients harbouring TP53 mutations were significantly more resistant to TKI compared to the wild type ones (86% vs 22%, P = 0.0045). It is worthy to note that the only patient with a TP53 mutation responsive to TKI carried a partially functional missense mutation (p.H214Y), as reported in the IARC TP53 database. Patients with undifferentiated TC (PDTC and ATC) were more frequently mutated in TP53 than those with WDTC (66.7% vs 12.5%, P = 0.0157) and were more frequently resistant to TKIs than the WDTC group (83% vs 29%, P = 0.0256). Among WDTCs, those with TP53 mutations tended to be more frequently unresponsive, and among undifferentiated cases, those with TP53 mutations were totally unresponsive, suggesting that the resistance to TKI therapy might be correlated to the presence of TP53 mutations regardless of the grade of differentiation. Conclusions: We demonstrated for the first time in TC a correlation between the presence of inactivating mutations in TP53 gene and the development of resistance to TKI therapy in patients harbouring aggressive thyroid cancers. The testing for these mutations could be considered as a prerequisite to be obtained when deciding the opportunity to start or not a treatment with TKIs.