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.

Figure 1. The two mTOR complexes: components, regulation, substrates, and inhibition

The Ser/Thr kinase mTOR exists in two structurally and functionally distinct complexes, mTORC1 and mTORC2. The core essential components of each complex are shown. The activation state of mTORC1 is responsive to both nutrients and growth factors and is acutely sensitive to inhibition by rapalogs. Growth factors can also increase mTORC2 activity, but not all of its functions are growth factor-stimulated (Box 1). Rapalogs do not directly inhibit mTORC2, but can lead to dissociation and inhibition of the complex over time (Box 2). Both mTORC1 and mTORC2 are equally sensitive to mTOR kinase inhibitors. mTOR phosphorylates distinct downstream substrates within mTORC1 and mTORC2 and a few of the best established targets are shown (Box 1).

Figure 2. A network of oncogenes and tumor suppressors converge on the regulation of mTORC1

Some of the most common oncogenes (depicted in green), including receptor tyrosine kinases (RTKs), oncogenic fusion proteins formed by chromosomal translocations, PI3K, Akt, Ras and Raf, and tumor suppressors (depicted in red), including PTEN, NF1, and LKB1, lie within signaling pathways that share mTORC1 regulation as a downstream target. In normal cells, growth factors bind to and stimulate RTKs and G protein-coupled receptors (GPCR), which can activate mTORC1 through either the PI3K-Akt or Ras-Erk signaling pathways. These pathways converge to inhibit the TSC complex (TSC1, TSC2, and TBC1D7), resulting in the accumulation of GTP bound Rheb, which is a potent and essential activator of mTORC1. Other pathways including LKB1-AMPK and Wnt signaling also impinge on regulation of the TSC complex and Rheb. A parallel pathway exists for amino acid sensing that involves the Rag family of GTPases, which act as a heterodimer of RagA or B with Rag C or D, and are regulated by different upstream sensors of amino acids. Oncogenic mutations within this network are common in cancer, resulting in aberrant activation of mTORC1 signaling and its promotion of anabolic processes underlying cell growth and proliferation.

Figure 3. The role of sustained mTORC1 in resistance to targeted therapeutics

A simple model of the response and progression of a tumor treated with a therapeutic targeting the initial driving oncogenic pathway. Inhibitor A blocks Oncogene A (Onc-A), which attenuates signaling to multiple downstream effectors, including mTORC1. If the Onc-A pathway is the primary, non-redundant route to mTORC1, a robust anti-tumor response will be observed. Acquired resistance can develop due to bypass activation of a parallel pathway through Oncogene-B (Onc-B) resulting in sustained mTORC1 signaling in the presence of Inhibitor-A. This resistance can be overcome through combination therapy with an mTOR inhibitor in settings of both innate (i.e. initial non-responsive) and acquired resistance.