The mammalian target of rapamycin (mTOR) signalling pathway is a central regulator of metabolism in all cells. It senses intracellular and extracellular signals and nutrient levels, and coordinates the metabolic requirements for cell growth, survival, and proliferation. Genetic alterations that deregulate mTOR signalling lead to metabolic reprogramming, resulting in the development of several cancers including those of the head and neck. Gain-of-function mutations in EGFR, PIK3CA, and HRAS, or loss-of-function in p53 and PTEN are often associated with mTOR hyperactivation, whereas mutations identified from The Cancer Genome Atlas (TCGA) dataset that potentially lead to aberrant mTOR signalling are found in the EIF4G1, PLD1, RAC1, and SZT2 genes. In this review, we discuss how these mutant genes could affect mTOR signalling and highlight their impact on metabolic processes, as well as suggest potential targets for therapeutic intervention, primarily in head and neck cancer.

Signal transducer and activator of transcription 3 (STAT3) signaling is a major driver of colorectal cancer (CRC) growth, however therapeutics, which can effectively target this pathway, have so far remained elusive. Here, we performed an extensive screen for STAT3 inhibitors among a library of 1167 FDA-approved agents, identifying Ponatinib as a lead candidate. We found that Ponatinib inhibits STAT3 activity driven by EGF/EGFR, IL-6/IL-6R and IL-11/IL-11R, three major ligand/receptor systems involved in CRC development and progression. Ponatinib was able to inhibit CRC migration and tumor growth in vivo. In addition, Ponatinib displayed a greater ability to inhibit STAT3 activity and mediated superior anti-proliferative efficacy compared to five FDA approved SRC and Janus Kinase (JAK) inhibitors. Finally, long-term exposure of CRC cells to Ponatinib, Dasatinib and Bosutinib resulted in acquired resistance to Dasatinib and Bosutinib occurring within six weeks. However, acquired resistance to Ponatinib was observed after long-term exposure of >4 months. Overall, our results identify a novel anti-STAT3 property of Ponatinib and thus, Ponatinib offers a potential therapeutic strategy for CRC.