Abstract
Small cell lung cancer (SCLC) is a highly aggressive malignancy with few therapeutic advances in the treatment in recent decades. Based on a recent study that identified the spliceosome as a therapeutic vulnerability in MYC-driven breast cancers, we evaluated the efficacy of a spliceosome inhibitor in SCLC cell lines and analyzed the correlation with MYC status. Among 23 SCLC cell lines examined, eight showed high MYC protein expression (> 80% positive cells) by immunohistochemistry (IHC), while 10 cell lines demonstrated no staining for MYC. The remaining five cell lines showed weak staining (< 40% positive cells). All four cell lines that were previously demonstrated to have MYC gene amplification were positive for MYC by IHC. Four cell lines with high MYC expression and four with low MYC expression were used in further analysis. A spliceosome inhibitor, pladienolide B, showed high efficacy (IC50 < 12nM) in all eight cell lines tested, irrespective of the MYC IHC or MYC gene amplification status. We observed that the four cell lines with higher sensitivity to the spliceosome inhibitor were established from patients with prior chemotherapy. Therefore we chronically treated H1048 cells, that were established from a treatment-naïve patient, with cisplatin for 4 weeks, and found that H1048-cisplatin treated cells became more sensitive to pladienolide B. In conclusion, our in vitro results indicate that spliceosome inhibitors would be promising molecular target drugs in SCLC irrespective of the MYC status, especially in the second-line settings after an effective front-line chemotherapy.
Highlights
Small cell lung cancer (SCLC) accounts for about 15–20% of lung cancer diagnoses, and is one of the most aggressive type of cancer with high mortality
Deregulation of MYC has long been recognized as playing a role in human malignancies, including lung, breast, colon, and prostate cancers, Burkitt’s lymphoma and other hematological malignancies [15]
In mice models, functional inactivation of TP53 together with RB1 is sufficient for the development of SCLC, and MYC family member aberration occurs during SCLC progression [16]
Summary
Small cell lung cancer (SCLC) accounts for about 15–20% of lung cancer diagnoses, and is one of the most aggressive type of cancer with high mortality. Despite a recent development of molecular targeted therapy in non-small cell lung cancers [1], there have been few therapeutic advances in the treatment of SCLC in recent decades. The widely known genetic alterations in SCLC are inactivating mutation/deletion of TP53 and RB1 and amplification of MYC family genes [2,3,4,5]. Amplification of one of the MYC family genes, MYC ( known as MYCC), MYCL, or MYCN in a mutually exclusive manner, was PLOS ONE | DOI:10.1371/journal.pone.0172209. Spliceosome inhibition in small cell lung cancer Amplification of one of the MYC family genes, MYC ( known as MYCC), MYCL, or MYCN in a mutually exclusive manner, was PLOS ONE | DOI:10.1371/journal.pone.0172209 February 13, 2017
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