Emerging Role of mTOR in the Response to Cancer Therapeutics

Abstract

The movement toward precision medicine with targeted therapeutics for cancer treatment has been hindered by both innate and acquired resistance. Understanding the molecular wiring and plasticity of oncogenic signaling networks is essential to the development of therapeutic strategies to avoid or overcome resistance. The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) represents a highly integrated signaling node that is dysregulated in the majority of human cancers. Several studies have revealed that sustained mTORC1 inhibition is essential to avoid resistance to targeted therapeutics against the driving oncogenic pathway in a given cancer. Here we discuss the role of mTORC1 in dictating the response of tumors to targeted therapeutics and review recent examples from lung cancer, breast cancer, and melanoma.

mTOR pathway activation drives lung cell senescence and emphysema

“…Activation of mTOR contributes to proliferative lung diseases such as lung cancer and pulmonary hypertension (28)(29)(30)(31), but its potential involvement in degenerative lung diseases such as COPD has not been specifically investigated. Our evidence of mTOR overactivity and increased cell senescence in COPD, combined with the efficacy of rapamycin in decreasing both mTOR activity and cell senescence, point to mTOR activation as a major driver of cell senescence in lungs from patients with COPD.…”

mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability

“…It is important to note that our findings indicate that IMPDH inhibitors should not be used in combination with rapalogs, as their selective cytotoxic effects are dependent on sustained mTORC1 signaling. While the TSC tumor suppressors are only rarely mutated in sporadic cancers, a large network of the most common oncogenes and tumor suppressors underlying human malignancies converge on regulation of the TSC complex (Ilagan, 2016). Thus, the TSC complex is predicted to be dysfunctional in at least half of human cancers, across nearly all lineages, due to perturbations in upstream signaling pathways, leading to chronic activation of mTORC1.…”

The PI3K Pathway in Human Disease

“…An inverse correlation was also observed between the efficacy of alpelisib and phospho-S6 levels (a downstream target of mTORC1-S6K) after 28 days of treatment, indicating that inhibition of mTORC1 activity is pivotal for the antitumor activities of p110α inhibitors. Interestingly, persistent mTORC1 activity also predicts resistance to RAF or MEK inhibitors in BRAF -mutant melanoma models (Corcoran et al, 2013), indicating that drug-refractory mTORC1 activation confers broad-based resistance to both PI3K/mTOR pathway- and Ras pathway-targeted agents (Ilagan and Manning, 2016). …”

“…Activation of the PI3K/mTOR is a common mediator of resistance to numerous anticancer agents, including conventional chemotherapy and agents targeting other oncogenic nodes (Brown and Toker, 2015; Ilagan and Manning, 2016). Emerging evidences points to PI3K/mTOR signaling as a mechanism of resistance to cancer immunotherapy.…”