SUMMARY Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low “variant” subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which combined with chemotherapy strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a potential targeted treatment approach for MYC-driven SCLC.

It has been reported that sleeve lobectomy (SL) concomitant with or without pulmonary artery reconstruction (PAR) might be an alternative procedure for pneumonectomy (PN) in non-small cell lung cancer (NSCLC). The aim of this study was to assess whether SL or PN offers a low morbidity and mortality and better long-term survival. We performed a meta-analysis of studies published in English between 1996 and 2006 to comprehensively compare the postoperative mortality, morbidity, locoregional recurrences, and time-to-event outcomes of SL and PN in NSCLC, and reviewed the recent literatures on PAR in the corresponding period as well. Twelve studies met the defined criteria including a total of 2984 subjects, and five studies for PAR. The odds ratio for postoperative mortality (SL vs PN) was 0.65 (95% confidence interval (CI): 0.42-1.01), 1.01 (95% CI: 0.70-1.44) for postoperative complications, and 0.91 (95% CI: 0.45-1.82) for locoregional recurrences. The weighted mean operative mortality for PAR was 3.3%, and 32.4% for complications. The estimated combined hazard ratio for overall survival in 10 studies was 0.70 (95% CI: 0.62-0.79) in favor of SL group. The median overall survival was 60 months for the SL group, 26 months for the PN group, and 30 months for PAR group. Survival difference in patients with pN0 or pN1 at 1 year demonstrated a pooled risk difference (SL vs PN) of 0.03 (95% CI: -0.08-0.13), 0.13 (95% CI: 0.00-0.25) in patients with pN2 at 1 year, 0.21 (95% CI: 0.07-0.36) in patients with pN0 or pN1 at 5 years, and 0.06 (95% CI: -0.10-0.21) in patients with pN2 at 5 years. Our results suggests that SL with or without PAR can be accomplished safely in selected patients without increasing the morbidity and mortality as compared to PN, that SL even with PAR offers better long-term survival than does PN, and that a more radical operation such as PN is not a more appropriate procedure, even in higher stage tumors.

Nearly all patients with small cell lung cancer (SCLC) eventually relapse with chemoresistant disease. The molecular mechanisms driving chemoresistance in SCLC remain un-characterized. Here, we describe whole-exome sequencing of paired SCLC tumor samples procured at diagnosis and relapse from 12 patients, and unpaired relapse samples from 18 additional patients. Multiple somatic copy number alterations, including gains in ABCC1 and deletions in MYCL, MSH2, and MSH6, are identifiable in relapsed samples. Relapse samples also exhibit recurrent mutations and loss of heterozygosity in regulators of WNT signaling, including CHD8 and APC. Analysis of RNA-sequencing data shows enrichment for an ASCL1-low expression subtype and WNT activation in relapse samples. Activation of WNT signaling in chemosensitive human SCLC cell lines through APC knockdown induces chemoresistance. Additionally, in vitro-derived chemoresistant cell lines demonstrate increased WNT activity. Overall, our results suggest WNT signaling activation as a mechanism of chemoresistance in relapsed SCLC.