Over-expression of p27kip1 induces growth arrest and apoptosis mediated by changes of pRb expression in lung malignancy cell lines. SCLC cell lines [9, 10], it is not obvious whether MYC suppression is sufficient to inhibit SCLC cell growth. Consequently, if the growth of human SCLC cells is not dependent on amplified family genes, MYC suppression would not be sufficient to have any therapeutic effect. In several mouse models of MYC-driven cancers, tumor regression by MYC suppression was hampered by the concomitant repression of TP53 or RB1 proteins, which highlighted the relevance of intact and pathways for the treatment of malignancy by MYC targeting [11C13]. In addition, since MYC proteins are overexpressed in SCLC cells, higher dose of MYC inhibitor administration would be required than in malignancy cells without family genes amplification. Alternatively, it is also possible that MYC suppression could be highly effective if SCLC cells are addicted to the expression of amplified family genes. Mutually unique amplification FGFR4-IN-1 of the three family genes and the concurrent expression of two or three family genes together, even though only one of them is usually amplified [14], imply the convenience of a common suppressing agent to all MYC proteins, MYC, MYCL and MYCN, to inhibit the growth of SCLC cells by MYC inhibition. MYC proteins are transcription factors with highly conserved and functionally important regions organized in FGFR4-IN-1 a similar manner among the three paralogs [15]. DNA-binding activity depends on a ~100 amino-acid carboxy-terminal region comprising the basic helix-loop-helix leucine zipper (bHLH-LZ) domain name that confers MYC proteins a highly specific conversation with another factor, Maximum. The heterodimer MYC-MAX binds DNA at E-Box sequences to drive transcription of numerous target genes. Furthermore, the MYC-MAX dimeric bHLH-LZ region forms a platform for the binding of other factors, such as MIZ1 (ZBTB17), FGFR4-IN-1 to repress transcription of a set of genes which share the initiatior (Inr) element at their promoter region [16]. Intriguingly, it has been recently reported that family genes, highlighting the relevance of MYC pathway in SCLC progression [17]. Soucek et al. developed a dominant-negative MYC, termed Omomyc, made up of MYC bHLH-LZ domain name with four amino acid substitutions that confer high binding affinity to both MYC and Maximum, as well as MYCN [18C20]. By competitive binding to both MYC and Maximum, Omomyc prevents NEK5 MYC-MAX heterodimerization and their conversation with the E-box. Consequently, overexpression of Omomyc inhibits the binding of MYC to DNA and transcription of target genes [20, 21]. Omomyc induces apoptosis and/or mitotic defects in MYC-driven papillomatosis [21], lung adenocarcinoma [22, 23], SV40-driven insulinoma [24], and glioblastoma [25]. Therefore, Omomyc is an efficient inhibitor of both MYC and MYCN. Although inhibition of MYCL by Omomyc has not been investigated, based on the similarity of MYCL with MYC/MYCN in protein structure, Omomyc could also inhibit MYCL, representing an excellent pan-MYC family inhibitor. To assess the potential of amplified family genes as therapeutic FGFR4-IN-1 target in SCLC, we investigated the effects of Omomyc on MYC inhibition in a panel of SCLC cell lines transporting genetic inactivation of and family genes. We show here that this inhibition of any MYC member by Omomyc induces cell growth arrest and/or apoptosis in SCLC cells even though both and are genetically inactivated. Notably, Omomyc also suppressed the growth of SCLC cells with amplification, and is able to interact with MYCL. Accordingly, we concluded that Omomyc is a pan-MYC family inhibitor, potentially useful for the treatment of SCLCs transporting any family member amplification. RESULTS Omomyc suppresses the growth and induces death of SCLC cells To investigate the functional impact of MYC inhibition by Omomyc in SCLC cells, we established an inducible Omomyc.