Figure 2 Signalling pathways and physiological domains that are

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Figure 2 Signalling pathways and physiological domains that are the focus of experimental targeted therapies for small-cell lung cancer (SCLC) Figure 2 | Signalling pathways and physiological domains that are the focus of experimental targeted therapies for small-cell lung cancer (SCLC). a | Dashed and solid lines indicate indirect and direct interactions, respectively. Proteins in green are typically upregulated in SCLCs compared with nonmalignant lung tissue, while those in red are downregulated or absent. Examples of the investigational molecularly targeted agents or antibody-based treatments targeting each signalling node are provided. b | The novel, investigational, targeted therapeutics for SCLC are predicated on five aspects of cancer biology. Immune-checkpoint blockade with antibodies targeting programmed cell death protein 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and/or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can prime the adaptive immune response to SCLC cells, whereas antibody-mediated blockade of the 'don't eat me' protein CD47 can enable phagocytosis of tumour cells by macrophages. The use of small-molecule inhibitors of key regulators of the cell cycle, such as the protein kinases WEE1 and aurora kinase A, exploits the inherent lack of the G1/S-checkpoint activity resulting from loss of the tumour suppressors p53 and retinoblastoma-associated protein (Rb) in most SCLC cells. WEE1 regulates the G2/M cell-cycle checkpoint that is essential for ensuring the integrity of the genome in such cancer cells and, thus, inhibition of this kinase can lead to mitotic catastrophe and apoptosis, particularly if combined with DNA-damaging therapies. By contrast, aurora kinase A has essential roles in mitosis, and inhibitors of this protein results in cell-cycle arrest, preventing cell proliferation. Inhibitors of Notch have demonstrated antitumour effects in preclinical studies. Moreover, Delta-like protein 3 (DLL3), an inhibitory Notch ligand, is specifically upregulated in SCLC and can, therefore, be leveraged for selective tumour targeting with the antibody–drug conjugate rovalpituzumab tesirine (Rova-T). Inhibitors of the histone-lysine N-methyltransferase EZH2 (also known as enhancer of zeste homologue 2), the enzymatic histone-lysine N-methyltransferase subunit of the polycomb repressive complex 2 (PRC2) chromatin-remodelling machinery, can prevent chemoresistance and cell proliferation by counteracting epigenetic gene silencing, in particular, of schlafen family member 11 (SLFN11) — a protein that negatively regulates homologous recombination DNA repair. Poly [ADP-ribose] polymerase (PARP) inhibitors prevent the activation of DNA-repair proteins by PARP1 and trap this enzyme on DNA, which causes further DNA damage that can eventually result in cell death. APC, antigen-presenting cell; ASCL1, achaete-scute homologue 1 (also known as ASH-1); Chk1/2, checkpoint kinase 1/2; E2F1, transcription factor E2F1 (also known as retinoblastoma-associated protein 1); PAR, poly-ADP-ribosylation. Sabari, J. K. et al. (2017) Unravelling the biology of SCLC: implications for therapy Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2017.71