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Fig. 1 | Journal for ImmunoTherapy of Cancer

Fig. 1

From: Immunotherapy in small-cell lung cancer: from molecular promises to clinical challenges

Fig. 1

Molecular landscape of SCLC. SCLC cells are characterized by ubiquitous loss of TP53 and Rb1 (dotted lines), the main G1-S cellular cycle checkpoints. SCLC cells depend on G2-M cell cycle checkpoint, that may be influenced by Aurora kinase A over-expression, characterizing the Myc-driven “variant” subtype of SCLC) and by Chk1-WEE1 axis. Chk1 is activated by Ataxia telangiectasia Mutated (ATM)/Ataxia telangiectasia and Rad-3 related protein (ATR) pathway upon chemo-induced DNA double strand break. After its activation, Chk1 can induce G2 cell cycle arrest through the phosphorylation of WEE1. Activated Chk1 can also up-regulate PD-L1 expression through the activation of the Signal Transducer and Activator of Transcription 1–3 (STAT1–3) mediated regulation of Interferon regulatory factor 1 (IRF1). Signaling pathways involving Enhancer of zeste homolog 2 (EZH2), an epigenetic modifier inducible both by immunotherapy and cytotoxic agents, also seem crucial in SCLC. EZH2 activity is required for the acquisition of an immunosuppressive phenotype, down-regulating antigen presentation process (resistance to immune-therapy), and also for an enhanced chemo-resistance property, through the inhibition of Schlafen family member 11 (SLFN11), a negative regulator of homologous repair machinery (HRM)

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