Listed in this section are

Listed in this p m x section are several studies where CRM1 inhibitors were used in combination with other cancer therapeutics and in drug-resistant/relapsed cancers. A table of current abstracts (Table 1) summarizes the latest findings in CRM1 combination therapies. In addition, we include a table on drug sequencing in the treatment of multiple myeloma (Table 2).
Funding Our study received valuable assistance from the Flow Cytometry Core Facility at the H. Lee Moffitt Cancer Center & Research Institute; an NCI designated Comprehensive Cancer Center, supported under NIH grant P30-CA76292. We especially thank Jodi Kroeger for her expert assistance with flow cytometry. This work was partially supported by the State of Florida Bankhead-Coley Team Science Project Grant 2BT03-43424. Experimental data presented in Table 2 contain lab results that were supported by Karyopharm Therapeutics (Natick, MA).
Conflicts of interest
Acknowledgements
Lung cancer continues to be the leading cause of cancer deaths in the US and worldwide., Non–small-cell lung cancer (NSCLC) remains the predominant form of lung cancer (approximately 85%)., With some improvements in surgical techniques and combined therapies over the past several decades, the relative survival rate for lung cancer has increased slightly. However, lung cancer remains extremely lethal, with a 5-year survival rate of only about 15% in the US. Unclear molecular mechanisms, lack of early diagnostic biomarkers, and deficiency of targeted therapy in lung cancer are some of the major reasons that its incidence, diagnosis, and prognosis remain relatively unchanged. Evidence shows that 80–90% of lung cancers are directly or indirectly traceable to tobacco use., , More than 60 known carcinogens have been identified in cigarette smoke,, among which N-nitrosamines play major roles in carcinogenesis. NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] is an important nitrosamine with highly carcinogenic activities and a consistent presence in relatively considerable amounts in cigarette smoke. NNK has been shown to have lung-selective toxicity and induce primarily lung adenocarcinoma in a variety of laboratory animals., The development of lung cancer has been extensively investigated in the past 40 years. Some of these studies, including our previous studies,, , have revealed a frequent occurrence of mutations in several proto-oncogenes and tumor suppressor genes, including p53 gene, and such alterations have been associated with the initiation and progression of lung cancer. In addition to mutations in oncogenes and tumor suppressor genes, accumulated evidence has also shown that stage-specific genes turn on or off during the process of cancer development. For instance, in eukaryotic cells nuclear-cytoplasmic transport is critical for normal biological functions, such as transcription and cell cycle regulation., Chromosome region maintenance 1 (CRM1), the best characterized nuclear export receptor, was first identified in the yeast and has been found as a conserved gene in eukaryotes. CRM1 protein, facilitated by Ran, plays an essential role in nuclear export signal (NES)-dependent nuclear export of various cancer-associated “cargo” proteins,, , , including both tumor suppressors and pro-oncogenes, which control genomic stability, cell cycle arrest, and apoptosis, such as p53, epidermal growth factor receptor (EGFR), protein kinase 1 (Akt1), survivin, and so on. The structure of CRM1 protein contains a highly conserved central region involved in RanGTP-dependent NES recognition and cysteine residue covalently modified by leptomycin B (LMB). LMB, an antifungal agent, is a highly specific and potent inhibitor of CRM1 function by irreversibly reacting with a Cys residue (Cys529) near or within the cargo binding domain of CRM1. Elevated CRM1 protein expression has been identified in various human tumors,, , , , but no study has been conducted on lung cancer.