Fig. 2
Mutated driver genes and downstream signal pathways in LSCC. FGFR1 amplification is observed in 20% of LSCC patients. FGFR1 amplifications can lead to overexpression of wild-type FGFR1 proteins on the cell membrane, resulting in increased sensitivity to FGF and the promotion of tumor growth via increased activation of four key downstream signaling pathways: PLCÎł, PI3K-AKT, RAS-MAPK, and STAT (green). Although mutations in EGFR gene are relatively rare in LSCC, in certain cases of LSCC these mutations are responsible for constitutive ligand-independent receptor activation and downstream signaling, promoting cell survival and proliferation. Mitogenic signaling, including activation of upstream PI3K and MAPK signaling, could drive cyclin D upregulation, which leads to CDK4/6 activation. The phosphorylation of RB by cyclin D-CDK4/6 complexes and cyclin E-CDK2 complexes releases E2F transcriptional factors to activate genes required for G1-S transition. The CDKN2A gene encodes p16INK4A and p14ARF, which regulate cell cycle by inhibiting CDK4/6 and CDK2, respectively. In LSCC, the inactivated CDKN2A caused by genomic alterations may upregulate this pathway. DAG diacylglycerol, E2F E2 family, FRS2 FGFR substrate 2, GRB2 growth factor receptor-bound 2, IP3 inositol triphosphate, MDM2 murine double minute 2, P phosphorylation, PIP2 phosphatidylinositol-4,5-biphosphate, PKC protein kinase C, PLCÎł phospholipase CÎł, PTEN phosphatase and tensin homolog, STAT signal transducer and activator of transcription
