ESMO 2014-PATHWAY OF THE DAY

Article extracted from the ESMO 2014 onsite newspaper.

The cyclin-dependent kinase (CDK) pathway (see Figure) is a series of complexes formed between cyclins and their associated kinases. This pathway, along with its inhibitors (e.g. p16 family proteins) and regulators (e.g. pocket proteins, checkpoint kinases and regulatory phosphatases), controls the orderly progression through each stage of the cell cycle via phosphorylation of specific substrates. CDK inhibitors and regulators are important for controlling this process and are therefore responsible for regulating cell proliferation. Several CDKs (e.g. CDK 4) have been identified in mammalian cells and are associated with specific cyclin partners.

Altered expression of some of the cyclins in the CDK pathway results in cancer development. Mantle cell lymphoma is characterised by high expression of cyclin D1, a G1-phase cyclin, which promotes cell cycle progression. Increased expression is secondary to the translocation of the BCL1 locus on chromosome 11 onto chromosome 14 (t[11;14][q13;q32]) and is exacerbated by mutations in cyclin D1 regulatory elements.1 When cyclin D1 is inhibited, cyclin D2 may come into play. Uveal melanoma is also a consequence of cyclin D1 overexpression. Furthermore, amplification of the cyclin D1 gene is observed in around 15–20% of breast cancers. A link has also been found between the presence of abnormally expressed CDK pathway-associated cyclins (e.g. cyclin D) and regulator proteins (e.g. p16, p21 and p57), and aggressive pathological features and poor clinical outcomes in clear cell renal cell carcinoma. 
A range of CDK inhibitors have entered clinical testing in cancer, including the broad range alvocidib and the highly specific CDK 4/6 inhibitor, palbociclib. Integral to the efficacy of CDK inhibitors will be the selection of the right inhibitor for the right target for any particular cancer and also the determination of whether optimal effects will be obtained with monotherapy or with a combination partner. Palbociclib is the selective CDK inhibitor at the most advanced stage of clinical investigation in cancer. It is currently in development as combination therapy with letrozole or exemestane for metastatic hormone receptor-positive breast cancer.2,3 Phase II trial results show that the palbociclib/letrozole combination improved progression-free and overall survival versus letrozole alone.2 Activity of palbociclib in relapsed mantle cell lymphoma has also been reported.4 Other CDK 4/6 inhibitors, LY2835219 and LEE011, are being investigated in early phase trials in breast cancer and malignant rhabdoid tumours, neuroblastoma and cyclin D CDK4/6 pathway-activated tumours, respectively.5,6 

1. Weniger MA, et al. Semin Hematol 2012;48:214–26
2. Finn RS, et al. AACR Annual Meeting; San Diego, California, USA: 5–9 April 2014. Abstract CT101
3. Martin M, et al. ESMO 2014:Abstract 409TiP
4. Leonard JP, et al. Blood 2012;119:4597–607
5. Geoerger B, et al. ESMO 2014:Abstract 455P
6. Patnaik A, et al. J Clin Oncol 2014;32(Suppl 5s):Abstract 534

Regulation of cell cycle checkpoint control. Adapted from Endocr Relat Cancer 2011; 18(4):C19-24