Finding the Right Path in Lung Cancer Therapy
Lung cancer is the biggest cancer killer worldwide, with historically low survival rates and a high number of cases caused by smoking. With targeted therapies now greatly improving treatment options, research is needed to uncover all of the mechanisms and oncogenes which are driving lung cancer forward. Newly published research has identified novel mutations that switch on major oncogenic pathways in lung cancer potentially putting scientists on the right path to new treatments and improved survival for this deadly disease.
Lung cancer is the most common cause of cancer death worldwide, accounting for more than 1 million deaths every year. This year it's estimated in the US alone that almost 160,000 people will die from lung cancer, which is over one-quarter of all US cancer deaths. Survival rates for the disease have historically been low, as patients are often diagnosed at a late stage where a cure is impossible. Recently, targeted therapies have improved treatment options for lung adenocarcinoma patients with activated oncogenes, with therapies such as gefitinib and erlotinib targeting EGFR and crizotinib targeting ALK. However, driving oncogene mutations remain to be identified for many other adenocarcinomas and other gene mutations give resistance to EGFR targeted agents, often leaving standard chemotherapy as the main treatment option.
Research published in Nature last month by The Cancer Genome Atlas Research Network is hoping to change this, by presenting the largest and most comprehensive genomic study of adenocarcinomas to date. The study analyzed samples from 230 lung adenocarcinoma patients using a wide variety of profiling techniques including messenger RNA, microRNA, DNA sequencing, and proteomic analysis. The work found mutations, fusions, chromatin modifications, and splicing alterations in the cancers, and used these to identify key pathways and potential driver oncogenes for the disease.
The main route that was identified in causing adenocarcinoma was the RTK/RAS/RAF pathway, which was initially shown to be activated or stuck on in 62% of patients with “common” pathway mutations, e.g. in KRAS, BRAF, and EGFR. The activated pathway continuously drives cancer cell proliferation, cell survival, and tumor growth. This finding is not particularly surprising, as many of the common mutations identified were already known in lung cancer, and gefitinib, erlotinib, and crizotinib already target members of the RTK/RAS/RAF pathway.
The researchers then turned their attention to patients without “common” RTK/RAS/RAF pathway mutations, to see if any previously unreported oncogenes could also be causing constitutive pathway activation. HER2 and MET amplifications, and NF1 and RIT1 mutations were found to be turning on the pathway in 14% of these patients and have now been put forward as potential driver oncogenes for these tumors. Targeting these new genes could provide novel treatment options in adenocarcinoma, and may provide alternative therapeutic routes to target the RTK/RAS/RAF pathway when resistance to initial therapies occurs. The research also highlights the importance of fully understanding tumor backgrounds and how many different mutations within the same tumor subtype can all work to activate the same oncogenic pathway.
Crown Bioscience supports research into different subtypes of lung cancer through the use of our large collection of clinically relevant Xenograft and Patient-Derived Xenograft (PDX) models available for drug discovery and translational sciences. We have the largest commercially available collection of PDX models (HuPrime®), which are well-characterized and are easily searchable through our free, online database (HuBase™) which can be used to identify relevant models to interrogate pathways, efficacy, and biomarkers. HuPrime contains a diverse collection of NSCLC PDX models with previously published “common” mutations in KRAS and EGFR which have an activated RTK/RAS/RAF pathway, and also includes models with NF1 mutations, MET amplifications, and ALK gene fusions. Our NSCLC models also have CDKN2A and STK11 mutations which were found in other activating pathways highlighted in this research, as well as FGFR gene fusions.
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