Formal Modeling of mTOR Associated Biological Regulatory Network Reveals Novel Therapeutic Strategy for the Treatment of Cancer

Zurah Bibi, Jamil Ahmad, Amnah Siddiqa, Rehan Z. Paracha, Tariq Saeed, Amjad Ali, Hussnain Ahmed Janjua, Shakir Ullah, Emna Ben Abdallah, Olivier Roux

Cellular homeostasis is a continuous phenomenon that if compromised can lead to several disorders including cancer. There is a need to understand the dynamics of cellular proliferation to get deeper insights into the prevalence of cancer. Mechanistic Target of Rapamycin (mTOR) is implicated as the central regulator of the metabolic pathway involved in growth whereas its two distinct complexes mTORC1 and mTORC2 perform particular functions in cellular propagation. To date, mTORC1 is a well defined therapeutic target to inhibit uncontrolled cell division, while the role of mTORC2 is not well characterized. Therefore, the current study is designed to understand the signaling dynamics of mTOR and its partner proteins such as PI3K, PTEN, mTORC2, PKB (Akt), mTORC1, and FOXO. For this purpose, a qualitative model of mTOR-associated Biological Regulatory Network (BRN) is constructed to predict its regulatory behaviors which may not be predictable otherwise. The depleted expression of PTEN and FOXO along with the overexpression of PI3K, mTORC2, mTORC1 and Akt is predicted as a stable steady state which is in accordance with their observed expression levels in the progression of various cancers. The qualitative model also predicts the homeostasis of all the entities in the form of qualitative cycles. The significant qualitative (discrete) cycle is identified by analyzing betweenness centralities of the qualitative (discrete) states. This cycle is further refined as a linear hybrid automaton model with the production (activation) and degradation (inhibition) time delays in order to analyze the real-time constraints for its existence. The analysis of the hybrid model provides a formal proof that during homeostasis the inhibition time delay of Akt is less than the inhibition time delay of mTORC2. In conclusion, our observations characterize that in homeostasis Akt is degraded with a faster rate than mTORC2 which suggests that the inhibition of Akt along with the activation of mTORC2 may be a better therapeutic strategy for the treatment of cancer.