Monday, 14 October 2013

Resistance to the leukemia treatment Imatinib can lay dormant and affect future treatment options

Normal cells that form the tissues of our body can be transformed into cancer by mutations within multiple genes that tell the cells how to behave. Mutations can come about in a number of different ways. Small changes in how a gene codes for just one of the amino acids that make up a protein can completely alter the activity of a protein. For example, KRas is a signalling protein with normally undergoes cyclical turning on and off when the cell needs it to help with growth, however a mutated active form a KRas cannot be turned off and goes on to allow cells to grow almost uncontrolled. Larger changes to genes may also occur with whole genes lost or moved around in the DNA. In fact in cancer cells DNA can become very messy!

A very important and well known mutation that was discovered in a leukaemia called chronic myelogenous leukemia (CML) is called the "Philadelphia Chromosome". This occurs when two large structures of DNA called chromosomes (humans have 23 pairs of chromosomes in each cell) swap small pieces; part of chromosome 9 is swapped with part of chromosome 22 making the former longer and the latter shorter. This new chromosome 22 is what is known as the "Philadelphia Chromosome". As a consequence, two genes BCR and ABL, which are not normally associated at the DNA level, become fused together to form the oncogene BCR-ABL. As an oncogene, BCR-ABL is crucial in driving cancer, it is most commonly associated with CML and other leukemias.

Many drugs for treating and managing cancer involve targeting a gene in cancer cells which is either found at a higher level or only slightly modified; because BCR-ABL is a completely different gene that is only found in cancer cells it was an attractive target for drug development. Indeed, an inhibitor of BCR-ABL called Imatinib/Gleevec has been immensely successful in treating CML. A number of patients respond well at first, but their cancer cells acquire a resistance to Imatinib; this occurs because the BCR-ABL protein becomes further mutated. Doctors can switch to using other BCR-ABL inhibitors such as Nilotinib/Tasigna, however some mutations in BCR-ABL also confer resistance to Nilotinib as well. 

A recent study in the British Cancer Journal found that mutations in BCR-ABL that become undetectable following treatment with Imatinib, can reemerge years later after treatment is changed to Nilotinib. This occurs in part due to a process called clonal expansion. A mutation which gives a cancer cell a growth or survival advantage compared to other cells within a tumour can be expanded, as these cells take over to form the bulk of the tumour.

It is therefore even more important for doctors to check which mutations of BCR-ABL are present in cancer cells when choosing treatment options, to prevent reemergence of mutations that will make cancer cells resistant.

Mentioned Articles

Parker WT, Yeoman AL, Jamison BA, Yeung DT, Scott HS, Hughes TP, Branford S.
Br J Cancer. 2013 Sep 17;109(6):1593-8. doi: 10.1038/bjc.2013.318

Cancer Research UK: Imatinib (Glivec)

Cancer Research UK: Nilotinib (Tasigna)

Sunday, 13 October 2013

Claudin 1 is a driver of EMT in primary liver cancer

Cancer of liver cells (hepatocellular carcinoma) is often diagnosed late as it may grow slowly and for unnoticed for years; consequently most patients present with advanced disease, the outlook for which is currently very poor. The process of epithelial to mesenchymal transition (EMT), which is required for many cancers to undergo metastasis and set up secondary tumours in other organs and tissues, occurs in advanced disease and in the case of liver cancer very little is known about EMT.

A recent study published in the journal Oncogene shows that a molecule that is normally involved in holding epithelial cells together in tissues, Claudin 1, can in fact promote EMT and allow cancer cells to become more invasive. Increased levels of Claudin 1 in liver cancer cells causes promotion of genes involved in EMT through up-regulation of key transcription factors ZEB1 and SLUG. Another important EMT transcription factor, SNAIL, was shown to not be involved, but interestingly a protein called c-Abl was found to be very important for this process.

c-Abl, is best known for being part of a mutation that occurs commonly in a form of leukaemia called CML and a number of drugs targeting c-Abl have been developed to treat CML. For example, Imatinib (Glivec) is an inhibitor that blocks the BCR-Abl fusion oncogene product which has been very useful for doctors  treating CML. In this present study, the group showed that by silencing the protein c-Abl in cells that have Claudin 1 over-expressed, they could reverse the up-regulation of ZEB1 and SLUG and prevent the invasiveness conveyed by EMT. This study demonstrates that in the future when doctors look at hepatocellular carcinoma they could look for increased levels of Claudin 1 as a possible indicator of the invasiveness of the cancer. With more work, this marker could be validated and possibly even exploited as a druggable target for the treatment of liver cancer.

Mentioned Articles

Suh Y, Yoon CH, Kim RK, Lim EJ, Oh YS, Hwang SG, An S, Yoon G, Gye MC, Yi JM, Kim MJ, Lee SJ.

Oncogene. 2013 Oct 10;32(41):4873-4882. doi: 10.1038/onc.2012.505.