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Lung cancer ALK and ROS1 oncogenes found in CRC tumours; therapeutic implications
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A research group in the University of Colorado Cancer Centre has found that the ALK and ROS1 gene rearrangements that characterise some subsets of lung cancer are also found in a subset of colorectal cancer (CRC) patients. The research group used fluorescence in situ hybridization (FISH) in a painstaking search of tumour samples from 236 patients from an Australian clinical trial. They discovered the ALK rearrangement in one patient and the ROS1 rearrangement in 2 patients. Surprisingly, results confounded conventional wisdom as not only did the group find that different regions of the same tumour had different oncogenic mutations but also in some regions more than one alteration was observed. For example ALK rearrangement co-existed with KRAS alteration while ROS1 mutations were observed to co-exist in one specimen with BRAF, another oncogenic mutation.

Although the number of CRC patients carrying these oncogenes was small, the significance for this subset of patients lies in the fact that there are FDA-approved drugs available, for example crizotinib, that were licenced to treat ALK-positive lung cancer which may now prove to be beneficial to some CRC patients also harbouring this mutation. Crizotinib belongs to a class of drugs known as tyrosine-kinase inhibitors (TKIs) which "turn off" ALK and ROS1 gene mutations and reduce cell proliferation. Although lung cancers harbouring ALK rearrangements eventually become resistant to crizotinib, there are other experimental drugs currently under development which may overcome this drawback, including Pfizer’s PF-06463922, which potently inhibits both ALK and ROS1 in mouse models of cancers driven by these oncogenes. The discovery of these mutations in CRC patients offers renewed hope that the therapeutic potential of such drugs may extend to subsets of CRC and other cancers.

Sources

AISNER, D.L., NGUYEN, T.T., PASKULIN, D.D., LE, A.T., HANEY, J., SCHULTE, N., CHIONH, F., HARDINGHAM, J., MARIADASON, J., TEBBUTT, N., DOEBELE, R.C., WEICKHARDT, A.J. and VARELLA-GARCIA, M., 2013. ROS1 and ALK Fusions in Colorectal Cancer, with Evidence of Intra-tumoral Heterogeneity for Molecular Drivers. Molecular Cancer Research, 2013. DOI: 10.1158/1541-7786.MCR-13-0479-T

University of Colorado Cancer Center. "Study finds known lung cancer oncogenes also drive colorectal cancer." ScienceDaily, 17 Dec. 2013. [Accessed 17 Dec. 2013].

American Association for Cancer Research. "Targeted investigational therapy potential to overcome crizotinib resistance in lung cancers." ScienceDaily, 20 Oct. 2013. [Accessed 17 Dec. 2013].

American Society for Radiation Oncology. "Crizotinib reduces tumor size in patients with ALK positive lung cancer." ScienceDaily, 6 Sep. 2012. [Accessed 17 Dec. 2013].
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Lung cancer ALK and ROS1 oncogenes found in CRC tumours; therapeutic implications00