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
ReviewKRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer
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
References (79)
- et al.
Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study
Lancet Oncol
(2005) - et al.
Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis
Lancet Oncol
(2010) - et al.
Status of PI3K inhibition and biomarker development in cancer therapeutics
Ann Oncol
(2010) - et al.
PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations
Neoplasia
(2008) - et al.
A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer
Cancer Cell
(2007) - et al.
PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients
Cancer Cell
(2004) - et al.
Molecular co-expression of the c-Met oncogene and hepatocyte growth factor in primary colon cancer predicts tumor stage and clinical outcome
Cancer Lett
(2007) - et al.
Investigation of the prognostic value of coexpressed erbB family members for the survival of colorectal cancer patients after curative surgery
Eur J Cancer
(2002) - et al.
Flt-1-dependent survival characterizes the epithelial-mesenchymal transition of colonic organoids
Curr Biol
(2003) - et al.
Targeting the RAF–MEK–ERK pathway in cancer therapy
Cancer Lett
(2009)
Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner
Cancer Cell
EGFR antagonists in cancer treatment
N Engl J Med
Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer
N Engl J Med
Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study
Clin Cancer Res
Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer
J Clin Oncol
Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab
J Clin Oncol
Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab
J Clin Oncol
Pharmacogenomic and pharmacoproteomic studies of cetuximab in metastatic colorectal cancer: biomarker analysis of a phase I dose-escalation study
J Clin Oncol
Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab
J Clin Oncol
Additional value of EGFR downstream signaling phosphoprotein expression to KRAS status for response to anti-EGFR antibodies in colorectal cancer
Int J Cancer
American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy
J Clin Oncol
BRAF wild-type is required for response to panitumumab or cetuximab in metastatic colorectal cancer
J Clin Oncol
Cetuximab plus FOLFIRI: final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome
Proc Am Soc Clin Oncol
PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies
Cancer Res
PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer
Clin Cancer Res
PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients
Br J Cancer
PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer
J Clin Oncol
Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer
J Clin Oncol
Phosphatidylinositol-3-OH kinase as a direct target of Ras
Nature
CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer
Gut
Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival: a population-based study
Cancer Epidemiol Biomarkers Prev
KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer
Cancer Res
Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab
JAMA
V600E BRAF is associated with disabled feedback inhibition of RAF–MEK signaling and elevated transcriptional output of the pathway
Proc Natl Acad Sci USA
Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers
Cancer Res
Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial
J Clin Oncol
Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signalling network correlate with poor survival in a population-based series of colon cancers
Int J Cancer
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These authors contributed equally