Colorectal Cancer

BRAFV600E as a Therapeutic Target in Colorectal Cancer

Jeanne Tie1 and Jayesh Desai2

1. Medical Oncology Research Fellow, Ludwig Colon Cancer Initiative Biomarker Laboratory, Ludwig Institute for Cancer Research, Melbourne; 2. Medical Oncologist, Department of Medical Oncology, Royal Melbourne Hospital and Peter MacCallum Cancer Institute, Melbourne

Abstract

Colorectal cancer is a major cause of cancer death in developed countries. Increasing knowledge of the underlying signalling pathways and molecular defects involved in carcinogenesis has led to the development of a multitude of novel target-based therapeutics. The Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signalling pathway plays a critical role in colorectal cancer progression. Therefore, targeting components of this pathway has been the subject of intense therapeutic effort. BRAF, a principal effector of Ras in this signalling cascade, was found to be mutated in a variety of cancers, including a small percentage of colorectal cancers. This article summarises the rationale for targeting BRAFV600E in colorectal cancer, a potential strategy to enrich the colorectal cancer population for the BRAFV600E mutation, and the prognostic and predictive role of BRAFV600E mutations in metastatic colorectal cancer.

Keywords

Colorectal cancer, BRAF, prognostic biomarker, predictive biomarker, mitogen-activated protein kinase (MAPK) signalling pathway, therapeutic target, BRAF inhibitor

Disclosure: The authors have no conflicts of interest to declare. Their study was a collaborative project with Plexxikon and Roche Molecular Systems. Received: 1 September 2009 Accepted: 13 October 2009 Citation: European Oncology, 2010;6(1):60–4 Correspondence: Jayesh Desai, Ludwig Colon Cancer Initiative Biomarker Laboratory, Ludwig Institute for Cancer Research, PO Box 2008 Royal Melbourne Hospital, Parkville, Victoria 3050, Australia. E: jayesh.desai@ludwig.edu.au

Colorectal cancer is the third most common cancer worldwide and the second leading cause of cancer deaths in the developed world,1,2

with

an estimated 149,000 new cases and 50,000 deaths each year in the US.3

Considerable progress has been achieved in the systemic treatment of colorectal cancer over the last decade with the incorporation of new chemotherapeutic (oxaliplatin and irinotecan) and biologic agents (bevacizumab, cetuximab and panitumumab) to the backbone of fluorouracil (5-FU)-based therapy. This has resulted in an improvement in median survival from 10–12 months to over 20 months for patients with metastatic colorectal cancer.4

Advances in molecular

biology have also allowed a more in-depth understanding of the genetic/epigenetic perturbations and the signal transduction pathways involved in colorectal cancer, leading to an appreciation of the molecular diversity in colorectal cancer. Nonetheless, until recently, colorectal cancer was treated as a single disease with a ‘one size fits all’ approach. Using KRAS mutation status to select patients against anti-epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy represents the first step towards personalising treatment in colorectal cancer, where treatment is guided by a tumour’s molecular profile.5–8

The Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) pathway is a critical signal transduction pathway involved in many cancers, including colorectal cancer, and has been the target of therapeutic intervention in recent years.9

However, therapeutic

efforts against Ras have thus far been unsuccessful in the clinic. This has led to interest in Raf kinase, in particular the BRAF oncogene, which is immediately downstream of Ras in the MAPK cascade. A

60

specific BRAFV600E inhibitor has now entered into early-phase clinical development in melanoma and colorectal cancer expressing the BRAFV600E mutation.10

However, the therapeutic development of BRAF

inhibitors in colorectal cancer will be challenging due to the low frequency of BRAFV600E mutations (approximately 10%) in this disease. This article will highlight the role of the MAPK pathway in colorectal cancer and BRAFV600E as a molecular target. We will also address the potential of enriching a colorectal cancer patient population for BRAFV600E mutations based on clinical features and the influence of BRAFV600E mutations on patient outcome.

Mitogen-activated Protein Kinase Signalling, BRAF Mutations and Colorectal Cancer

The MAPK signalling cascade functions immediately downstream of cell surface receptors and cytoplasmic signalling proteins, relaying extracellular signals to transcriptional regulation of fundamental cellular functions such as growth, survival, proliferation, differentiation and migration.11–13

This pathway is deregulated in

about 30% of all human cancers and can be activated by mutations in oncogenes such as KRAS and BRAF, or activation of upstream receptor tyrosine kinases such as EGFR (see Figure 1). The ‘oncogenic addiction’ of the MAPK pathway in colorectal cancer is reflected by the frequent perturbation of this pathway in this malignancy, with EGFR overexpression reported in about 50% of

cases14,15

and activating mutations in KRAS and BRAF reported in 30–50 and 10% of cases, respectively.16-19

The oncogenic role of

KRAS is well described in the stepwise model of colorectal carcinogenesis and will not be discussed in this article.20–22

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