Growth suppression by MYC inhibition in small cell lung cancer cells with TP53 and RB1 inactivation

Fiorentino, Francesco Paolo; Tokgün, Elvan; Solé-Sánchez, Sònia; Giampaolo, Sabrina; Tokgün, Onur; Jauset, Toni; Kohno, Takashi; Perucho, Manuel; Soucek, Laura; Yokota, Jun

doi:10.18632/oncotarget.8826

Cited by 58 publications

(51 citation statements)

References 47 publications

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“…Other than SCLC, amplification and/or expression of MYCL have been detected only in ovarian and gastric cancer [32, 33], although its biological significance is still unknown. We and others have demonstrated the growth inhibition of SCLC cells in vitro by blocking MYCL [6, 34]. Thus, this and previous studies point to MYCL as a promising target of therapy specifically in SCLC patients.…”

Section: Discussionsupporting

confidence: 56%

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MYCL is a target of a BET bromodomain inhibitor, JQ1, on growth suppression efficacy in small cell lung cancer cells

et al. 2016

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We aimed to elucidate the effect of JQ1, a BET inhibitor, on small cell lung cancers (SCLCs) with MYCL amplification and/or expression. Fourteen SCLC cell lines, including four with MYCL amplification, were examined for the effects of JQ1 on protein and gene expression by Western blot and mRNA microarray analyses. The sensitivity of SCLC cells to JQ1 was assessed by cell growth and apoptosis assays. MYCL was expressed in all the 14 cell lines, whereas MYC/MYCN expression was restricted mostly to cell lines with gene amplification. ASCL1, a transcription factor shown to play a role in SCLC, was also expressed in 11/14 cell lines. All SCLC cell lines were sensitive to JQ1 with GI50 values ≤1.23 μM, with six of them showing GI50 values <0.1 μM. Expression of MYCL as well as MYCN, ASCL1 and other driver oncogenes including CDK6 was reduced by JQ1 treatment, in particular in the cell lines with high expression of the respective genes; however, no association was observed between the sensitivity to JQ1 and the levels of MYCL, MYCN and ASCL1 expression. In contrast, levels of CDK6 expression and its reduction rates by JQ1 were associated with JQ1 sensitivity. Therefore, we concluded that CDK6 is a novel target of JQ1 and predictive marker for JQ1 sensitivity in SCLC cells.

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Section: Discussionsupporting

confidence: 56%

“…Lysate preparation and Western blot analyses were performed as described previously [34]. Antibodies used are MYCL (AF4050, R&D), MYC (sc-40, Santa Cruz), MYCN (#9405, Cell Signaling), MAX (sc-197, Santa Cruz), ASCL1 (556604, BD Pharmingen), p21 (#2947, Cell Signaling), PARP-1 (#9542, Cell Signaling), and α-Tubulin (CP06, CalBiochemicals).…”

Section: Methodsmentioning

confidence: 99%

MYCL is a target of a BET bromodomain inhibitor, JQ1, on growth suppression efficacy in small cell lung cancer cells

et al. 2016

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“…Of interest, it may present pan‐cancer patterns of somatic copy number alterations . Amplification of the MYC family genes MYC and MYCL (1p34.2) is common in lung cancers, and narrow band gains of both genes were noted in LUADs and LUSCs.…”

Section: Resultsmentioning

confidence: 99%

Genome‐wide copy number variation pattern analysis and a classification signature for non‐small cell lung cancer

Qiu

Gazdar

et al. 2017

Genes Chromosomes & Cancer

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The accurate classification of non-small cell lung carcinoma (NSCLC) into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) is essential for both clinical practice and lung cancer research. Although the standard WHO diagnosis of NSCLC on biopsy material is rapid and economic, more than 13% of NSCLC tumors in the USA are not further classified. The purpose of this study was to analyze the genome-wide pattern differences in copy number variations (CNVs) and to develop a CNV signature as an adjunct test for the routine histopathologic classification of NSCLCs. We investigated the genome-wide CNV differences between these two tumor types using three independent patient datasets. Approximately half of the genes examined exhibited significant differences between LUAD and LUSC tumors and the corresponding non-malignant tissues. A new classifier was developed to identify signature genes out of 20 000 genes. Thirty-three genes were identified as a CNV signature of NSCLC. Using only their CNV values, the classification model separated the LUADs from the LUSCs with an accuracy of 0.88 and 0.84, respectively, in the training and validation datasets. The same signature also classified NSCLC tumors from their corresponding non-malignant samples with an accuracy of 0.96 and 0.98, respectively. We also compared the CNV patterns of NSCLC tumors with those of histologically similar tumors arising at other sites, such as the breast, head, and neck, and four additional tumors. Of greater importance, the significant differences between these tumors may offer the possibility of identifying the origin of tumors whose origin is unknown.

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“…Work by us and other groups also showed Omomyc to be an effective Myc dominant negative and included further co-immunoprecipitation (CoIP) experiments in human embryonic kidney 293T and small-cell lung cancer (SCLC) cells Lu135 and H2141, demonstrating the interaction of Omomyc with MYC, MYCL, and MYCN, therefore pointing to it as a potential pan-Myc inhibitor. Interaction with MAX and MIZ-1, but not the Myc antagonist MXD1 or other HLH proteins such as HEB, ID1, and HIF1-α was also detected [53,54]. This demonstrated the specificity of Omomyc for the Myc-MAX network, but not the rest of the PMN.…”

Section: Omomyc As a Myc Dominant Negativementioning

confidence: 83%

Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc

Massó-Vallés

Soucek

2020

Cells

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109

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First designed and published in 1998 as a laboratory tool to study Myc perturbation, Omomyc has come a long way in the past 22 years. This dominant negative has contributed to our understanding of Myc biology when expressed, first, in normal and cancer cells, and later in genetically-engineered mice, and has shown remarkable anti-cancer properties in a wide range of tumor types. The recently described therapeutic effect of purified Omomyc mini-protein-following the surprising discovery of its cell-penetrating capacity-constitutes a paradigm shift. Now, much more than a proof of concept, the most characterized Myc inhibitor to date is advancing in its drug development pipeline, pushing Myc inhibition into the clinic.

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Growth suppression by MYC inhibition in small cell lung cancer cells with TP53 and RB1 inactivation

Cited by 58 publications

References 47 publications

MYCL is a target of a BET bromodomain inhibitor, JQ1, on growth suppression efficacy in small cell lung cancer cells

MYCL is a target of a BET bromodomain inhibitor, JQ1, on growth suppression efficacy in small cell lung cancer cells

Genome‐wide copy number variation pattern analysis and a classification signature for non‐small cell lung cancer

Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc

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