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    • Akt mTOR signaling pathway is a major negative

    2022-07-22

    Akt/mTOR signaling pathway is a major negative regulator of autophagy, via modulating ULK1 complex. It is well established that Inhibition of mTOR by deprivation of nutrients or growth factors, led to dephosphorylation of ULK1, ULK2, and Atg13 in human cells, which is a key step for ULK1 complex assembly. Nevertheless, autophagy can also be activated and processed in an mTOR-independent pathway [27]. In present data, we showed that the Akt/mTOR pathway was markedly repressed in PD166866-treated cells, indicated by induced phosphorylation of Akt, mTOR and two mTOR downstream effectors, P70S6K and 4E-BP1. Further, restore of Akt/mTOR pathway by exogenous Octyl-α-ketoglutarate synthesis of ca-AKT markedly counteracted PD166866-induced autophagy and cell proliferation inhibition. Therefore, based on our data, it is reasonable to infer that PD166866 treatment might mimics deprivation of FGFs, and subsequently repressed Akt/mTOR pathway, finally leading to autophagy activation in FGFR1-amplified breast cancer cells.
    Conflicts of interest
    Acknowledgment This work was supported by grants from the National Natural Science Foundation of China (No. 81302205, No. 81402245), and Key Fund Project of Sichuan Provincial Department of Education (15ZA0250).
    Introduction Lung cancer is classified into two main histologic types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), accounting for 87% and 13% of all cases, respectively. The main histologic subtypes of NSCLC are adenocarcinoma (Ad-NSCLC, 50–60%), squamous cell carcinoma (Sq-NSCLC, 30–35%) and large-cell carcinoma (LCC, 5–10%) [1]. In the last years, potentially targetable oncogene products have been recognized in approximately 60% of Ad-NSCLC [2], [3], [4], [5]; conversely, Sq-NSCLC remains an “orphan” tumor to date; in fact, targeted agents have not yet been developed and chemotherapy continues to be the standard of care in this histotype [6]. By using high-throughput molecular technologies, ever-growing information about distinct genomic alterations in Sq-NSCLC are becoming available [7], [8]. Recently, the Cancer Genome Atlas Research Network reported an integrated analysis based on DNA copy number, exonic mutations, mRNA sequencing and expression and epigenetic alterations in 178 Sq-NSCLC samples [8]. A mean of 360 exonic mutations, 323 altered copy number segments and 165 genomic rearrangements per tumor was identified. SOX2 amplification, NFE2L2, KEAP1, discoidin domain receptor 2 (DDR2) mutations, phosphatidyl-inositol 3-kinase (PI3K) pathway changes and fibroblast growth factor receptor 1 (FGFR1) amplification, rare in Ad-NSCLC, confirmed the distinct molecular features of Sq-NSCLC. Potential druggable alterations were identified in 64% of cases. Among them, DDR2 mutation was reported in 1–4% of Sq-NSCLC and its sensitivity to dasatinib inhibition was demonstrated both in vitro and in vivo[9], [10]. Alterations in PI3K/AKT/mTOR pathway have shown to be mutually exclusive with EGFR ones (in contrast to that reported in Ad-NSCLC) and include PIK3CA mutations (3–10%) or amplification (25–40%), loss of PTEN (8–59%) or PTEN mutation (3–10%) and AKT1 or AKT2 overexpression (19% and 32%, respectively) [11]. Together with PI3K pathway, fibroblast growth factor receptor (FGFR) turns out as one of the most promising druggable target in Sq-NSCLC [12], [13].
    FGF–FGFR: structure, signaling and functions
    FGFR alterations in NSCLC In human cancers, FGF/FGFR signaling can be aberrantly activated as a result of ligand-dependent or ligand-independent mechanisms. FGFR gene amplifications, somatic missense mutations and chromosomal translocations, leading to receptor overexpression and/or constitutive FGFR or FGFR-TK activation; alternative splicing, leading to altered ligand–receptor specificity; paracrine/autocrine signaling, due to FGF upregulation, and FGFR germline single nucleotide polymorphisms (SNPs) are the most frequent mechanisms of activation [24]. Table 1 and Fig. 3 summarize the principal FGF/FGFR alterations in NSCLC cancers. In particular, in Sq-NSCLC, FGF/FGFR pathway has been recognized as one of the hallmark alterations with relevant clinical implications.