Anaplastic thyroid cancer (ATC) is one of the most lethal malignancies, with a median survival of less than 6 months from time of diagnosis.
Molecular changes that characterize ATC involve most often p53 loss or inactivation (up to 80%), activation of the PI3K cascade through PTEN loss (12%) and PIK3CA activating mutations (20%) or gene amplification (30-60%), RAS family members activation (6-50%), and BRAF activation (25-50%).
Studies performed in endometrial and breast cancer suggest that although PI3K activating mutations and PTEN loss of function both enhance PI3K signaling, these mutations are not equivalent.
We have tested whether Pik3caH1047R and Pten-/- mutations have the same impact on thyroid cancer development and if these two mutations differ in their ability to cooperate with additional genetic alterations, such as p53 deletion and the KrasG12D activating mutation.
We have generated a series of mouse models and cell lines carrying thyroid-restricted p53-/-, KrasG12D, Pten-/-, and Pik3caH1047R alleles.
Analysis of single and compound mutants has revealed important and striking differences between Pten and PI3K abilities to control the PI3K signaling pathway.
Tumor development analysis in Pten-/- and Pik3caH1047R mice has revealed that Pik3ca activation is less potent in inducing thyroid hyperplasia and subsequent transformation than Pten loss, even though the two mutations appear to have similar ability to induce AKT activation. This differential activity correlates with lower levels of PIP3 found in the thyroids of Pik3caH1047R mice, compared to that of Pten-/- mice.
We also observed that while Pten loss synergizes with Trp53 loss to induce anaplastic thyroid cancer, activation of Pik3ca leads to the development of a smaller and well differentiated tumors.
On the other hand, Pten loss and Pik3ca activation are equivalent in inducing poorly differentiated tumors in the presence of a Kras activating mutation.
However, KrasG12D, Pik3caH1047R cell lines are more sensitive to PI3K, MEK and combined PI3K/MEK inhibition than KrasG12D, Pten-/- cell lines.
Accordingly, tumors developing in mice carrying the KrasG12D, Pik3caH1047R alleles are more sensitive than KrasG12D, Pten-/- mice to a dual PI3K/mTor inhibitor as well as a MEK inhibitor.
All together these results suggest that Pten loss has a stronger impact than Pik3ca activation to thyroid cancer development and resistance to small molecule inhibitors.
Citation Format: Michela Ranieri, Antonio Di Cristofano. Differential role of Pik3caH1047R and Pten-/- mutations in thyroid cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2368. doi:10.1158/1538-7445.AM2017-2368