Elsevier

The Lancet Oncology

Volume 12, Issue 6, June 2011, Pages 594-603
The Lancet Oncology

Review
KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer

https://doi.org/10.1016/S1470-2045(10)70209-6Get rights and content

Summary

The discovery of mutant KRAS as a predictor of resistance to epidermal growth-factor receptor (EGFR) monoclonal antibodies brought a major change in the treatment of metastatic colorectal cancer. This seminal finding also highlighted our sparse knowledge about key signalling pathways in colorectal tumours. Drugs that inhibit oncogenic alterations such as phospho-MAP2K (also called MEK), phospho-AKT, and mutant B-RAF seem promising as single treatment or when given with EGFR inhibitors. However, our understanding of the precise role these potential drug targets have in colorectal tumours, and the oncogenic dependence that tumours might have on these components, has not progressed at the same rate. As a result, patient selection and prediction of treatment effects remain problematic. We review the role of mutations in genes other than KRAS on the efficacy of anti-EGFR therapy, and discuss strategies to target these oncogenic alterations alone or in combination with receptor tyrosine-kinase inhibition.

Introduction

Targeted drugs for the treatment of cancer have rapidly developed. However, our understanding (at the molecular level) of the precise role that potential targets have in tumorigenesis, and the survival dependence that tumours have on these components, has not progressed at the same rate. Therefore, patient selection remains problematic—eg, less than 20% of patients with metastatic colorectal cancer (mCRC) respond to clinically available targeted drugs when used as monotherapy.1, 2 Clearly, individualised treatment is needed. Colorectal cancer is a heterogeneous disease defined by different activating mutations in receptor tyrosine kinases (RTKs), or activating or loss-of-function mutations in downstream components of RTK-activated intracellular pathways, some of which can occur in the same tumour. The efficacy of targeted drugs is therefore linked to the specific molecular alterations in the tumour. The epidermal growth-factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab are highly effective in a subset of patients with mCRC. In this Review, we describe key components of the EGFR-signalling pathway that are altered in mCRC and the potential therapeutic efficacy of selective molecularly targeted drugs.

Section snippets

Molecular mechanisms of primary resistance to EGFR antibodies

EGFR (also called ERBB1/HER1) is an RTK belonging to the ERBB-family. Cetuximab and panitumumab block ligand-induced EGFR tyrosine-kinase activation, thereby probably preventing downstream activation of phosphatidylinositol 3-kinase (PI3K)/AKT and RAS/MAP2K (also called MEK)/MAPK1/3 (also called ERK2/1) signalling pathways (figure), resulting in inhibition of cellular proliferation and induction of apoptosis.1 A series of genetic and biological characteristics of colorectal cancer thought to be

Acquired resistance to EGFR antibodies

Patients with mCRC that initially respond to EGFR monoclonal antibodies eventually become resistant to these drugs. The duration of response depends on the time that it takes cancer cells to develop resistance mechanisms. Resistance might occur through the selection of clones that are resistant at the start of treatment, or the development of acquired resistance in cancer cells that are initially sensitive to treatment. Various molecular mechanisms are likely to have a role in acquired

Targeted therapies

To overcome resistance to EGFR monoclonal antibodies in patients with mCRC, novel targeted therapies are being extensively tested in the preclinical setting and are rapidly entering clinical trials. However, prediction of who will benefit from these novel drugs will be more difficult than first anticipated.

Conclusion

Personalised cancer medicine based on genetic profiling of individual tumours is regarded as the treatment strategy of the future. The discovery of mutant KRAS as a predictor of resistance to EGFR monoclonal antibodies has brought this approach into clinical practice in mCRC. However, this seminal finding is only the beginning of a series of novel predictive tools that will affect treatment choices in mCRC. Evidence shows that other molecular alterations, such as BRAF and PIK3CA (exon 20)

Search strategy and selection criteria

We searched PubMed and references from relevant articles with the search terms “cetuximab”, “mTOR inhibitor”, “MEK inhibitor”, “BRAF inhibitor”, “PI3K inhibitor”, “PTEN”, “EGFR”, “resistance”, “panitumumab”, “tyrosine kinase inhibitors”, and “colorectal cancer”. Only articles published in English were included. The search strategy was not limited by date. We also visited the website http://www.clinicaltrials.gov on March 1, 2010, to check for recent clinical trials of the targeted therapies of

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