A Genetic Snapshot of Small Cell Lung Cancer

Abstract

Small cell lung cancer (SCLC) represents 13% of all newly diagnosed cases of cancer worldwide, or more than 180,000 cases per year. In contrast with non-small cell lung cancer (NSCLC), it is not associated with specifi c somatic mutations ( 1 ). The prognosis for patients with SCLC has not improved and treatment has remained substantially the same for the last 25 years. The fi rst-line treatment of choice in extensivestage SCLC is 4 to 6 cycles of etoposide combined with cisplatin or carboplatin, with a median survival of 8 to 13 months and a 2-year survival rate of 5%. For patients with limitedstage disease, the standard treatment is the same chemotherapy regimen with the addition of thoracic radiotherapy, and median survival is 15 to 20 months, with a 2-year survival rate of 20% to 40% ( 1 ). The RB and TP53 tumor suppressor genes are both mutated in more than 90% of human SCLCs. Recent data indicate that p130 mRNA levels are downregulated in SCLC. Similarly, loss of E2F4, a major partner for p130, partially suppresses lung neuroendocrine hyperplasias in RBmutant mice. The loss of p130 accelerates the development of SCLC in RB / TP53 -mutant mice ( 2 ).In this issue of Cancer Discovery , Byers and colleagues ( 3 ) identify signifi cant differences in signaling pathways between SCLC and NSCLC. Using reverse phase protein arrays, they studied the expression of 193 proteins in 34 SCLC and 74 NSCLC cell lines. PARP1 and enhancer of zeste homolog 2 (EZH2) were 2 of the most overexpressed proteins in SCLC. SCLC growth was abrogated by knockdown of PARP1 and EZH2. Intriguingly, SCLC cell lines were signifi cantly more sensitive to PARP inhibitors than were NSCLC cell lines. PARP inhibition downregulated key components of the homologous recombination pathway, such as RAD51 and BRCA1. The authors observed lower levels of total and IN THE SPOTLIGHT A Genetic Snapshot of Small Cell Lung Cancer Commentary on Byers et al., p. 798 (3).phospho-Rb and higher levels of E2F1 in SCLC than in NSCLC cell lines. They posit that because of the loss of RB, E2F1 expression leads to the activation of several E2F1 targets in SCLC cells, such as EZH2, thymidylate synthase (TS), and several components of DNA repair pathways, including 53BP1 ( 3 ). In contrast, NSCLC cells had higher expression of receptor tyrosine kinases that heterodimerize with EGFR, including HER2, MET, and AXL. The differential expression of PARP1 was confi rmed by Western blotting and by mRNA analysis. The mRNA levels in SCLC were higher for PARP1, EZH2, BCL2, PRKDC (DNA PKcs), and proliferating cell nuclear antigen ( PCNA ). PARP1 expression was also examined in 318 cell lines derived from 30 types of primary cancer. Interestingly, SCLC cells showed the highest PARP1 expression. Immunohistochemistry confi rmed that PARP1 was more highly expressed in SCLC than in NSCLC. The most intriguing fi nding is that the majority of SCLC cells were sensitive to the use of PARP inhibitors, such as AZD2281, in contrast to the majority of NSCLC cell lines, which were resistant, i...

Dual MET and SMO Negative Modulators Overcome Resistance to EGFR Inhibitors in Human Nonsmall Cell Lung Cancer

“…Interestingly, in the presence of SAG, the induced inhibition of GLI1 activity was completely reverted in almost all treatments at a 2 μM concentration of We analyzed the activity of 5 and 11 in the EGFR-mutated HCC827-GR NSCLC cells with the already described amplification of SMO and overexpression of MET and displaying a typical mesenchymal behavior. 7 In this model, as already demonstrated, activation of AXL (phospho-AXL), which is a known pathway responsible for the acquisition of resistance to anti-EGFR TKIs and mediator of EMT, 29 and another signaling pathway potentially activated as a resistance mechanism, was not significantly high as compared to sensitive cell models. 7 We first evaluated the antiproliferative effects at different concentrations of 5 and 11 by using an MTT assay.…”

“…We analyzed the activity of 5 and 11 in the EGFR -mutated HCC827-GR NSCLC cells with the already described amplification of SMO and overexpression of MET and displaying a typical mesenchymal behavior . In this model, as already demonstrated, activation of AXL (phospho-AXL), which is a known pathway responsible for the acquisition of resistance to anti-EGFR TKIs and mediator of EMT, and another signaling pathway potentially activated as a resistance mechanism, was not significantly high as compared to sensitive cell models …”

SOX2 mediates cisplatin resistance in small‐cell lung cancer with downregulated expression of hsa‐miR‐340‐5p

“…The conventional treatment options for SCLC with cisplatin have remained unchanged despite the development of drug resistance and increased mortality with a reduced overall median survival rate (Tripathi et al, 2017;Umemura et al, 2014). Even though SCLC management has followed the major developments of modern cancer treatment through the integration of biology, imaging, chemotherapy, and radiotherapy, the prognostic improvement and treatment has remained substantially the same for the past 25 years (Karachaliou et al, 2013;Rosell & Wannesson, 2012).…”

‘Two-faces’ of hyaluronan, a dynamic barometer of disease progression in tumor microenvironment

“…Tumourigenesis attributes to various genetic mutations, one of the important mutation types is the deletion of the coding region in chromosomes which is highly related to the occurrence of tumor [97]. Apart from all types of tumors, there is a major susceptible deletion of hyaluronidases whose coding sequence located in chromosome 3p21.3 across ethnics and countries that contributed to lung cancer [97][98][99][100][101][102]. Major mutations of various 3p regions found in many cohorts of LC were the deletion of which the sequence of hyaluronidase (HYAL) 1 2 and 3 was located [103][104][105].…”