A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers1. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug2. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood3, 4, 5, 6, 7, 8. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.
At a glance
- EGFR antagonists in cancer treatment. N. Engl. J. Med. 358, 1160–1174 (2008) &
- K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 359, 1757–1765 (2008) et al.
- Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene 27, 3944–3956 (2008) et al.
- Establishment and characterization of a model of acquired resistance to epidermal growth factor receptor targeting agents in human cancer cells. Clin. Cancer Res. 15, 1585–1592 (2009) et al.
- Nuclear EGFR contributes to acquired resistance to cetuximab. Oncogene 28, 3801–3813 (2009) , , , &
- Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma. PLoS ONE 5, e12702 (2010) et al.
- Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci. Transl. Med. 3, 99ra86 (2011) et al.
- Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nature Med. 18, 221–223 (2012) 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. 6, 279–286 (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. 11, 753–762 (2010) et al.
- Circulating mutant DNA to assess tumor dynamics. Nature Med. 14, 985–990 (2008) et al.
- Replacement of normal with mutant alleles in the genome of normal human cells unveils mutation-specific drug responses. Proc. Natl Acad. Sci. USA 105, 20864–20869 (2008) et al.
- Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J. Clin. Oncol. 28, 1254–1261 (2010) &
- Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408–1417 (2009) et al.
- Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 1626–1634 (2008) et al.
- Challenges of detecting EGFR T790M in gefitinib/erlotinib-resistant tumours. Lung Cancer 60, (suppl. 2)S3–S9 (2008)
- Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J. Clin. Invest. 116, 2695–2706 (2006) et al.
- Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin. Cancer Res. 17, 1169–1180 (2011) et al.
- Increased detection sensitivity for KRAS mutations enhances the prediction of anti-EGFR monoclonal antibody resistance in metastatic colorectal cancer. Clin. Cancer Res. 17, 4901–4914 (2011) et al.
- A colon cancer cell line (LIM1215) derived from a patient with inherited nonpolyposis colorectal cancer. J. Natl. Cancer Inst. 74, 759–765 (1985) , , &
- Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours - implications for personalised cancer medicine. Br. J. Cancer 102, 693–703 (2010) et al.
- Supplementary Information (3.5M)
This file contains Supplementary Figures 1-7 and Supplementary Tables 1-4.