Blog
About

  • Record: found
  • Abstract: found
  • Article: not found

The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers

Read this article at

ScienceOpenPublisherPMC
Bookmark
      There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

      Abstract

      Colorectal tumors that are wild-type (WT) for KRAS are often sensitive to EGFR blockade, but almost always develop resistance within several months of initiating therapy 1, 2 . The mechanisms underlying this acquired resistance to anti-EGFR antibodies are largely unknown. This situation stands in marked contrast to that of small molecule targeted agents, such as inhibitors of ABL, EGFR, BRAF, and MEK, in which mutations in the genes encoding the protein targets render the tumors resistant to the effects of the drugs 36 . The simplest hypothesis to account for the development of resistance to EGFR blockade are that rare cells with KRAS mutations pre-exist at low levels in tumors with ostensibly WT KRAS genes. Though this hypothesis would seem readily testable, there is no evidence in pre-clinical models to support it, nor is there data from patients. To test this hypothesis, we determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. We found that nine of 24 (38%) patients whose tumors were initially KRAS WT developed detectable mutations in KRAS in their sera, three of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between five to six months following treatment. Mathematical modeling indicated that the mutations were present in expanded subclones prior to the initiation of panitumumab. These results suggest that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a non-invasive manner. Moreover, they explain why solid tumors develop resistance to targeted therapies in a highly reproducible fashion.

      Related collections

      Most cited references 30

      • Record: found
      • Abstract: found
      • Article: not found

      MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.

      The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.
        Bookmark
        • Record: found
        • Abstract: found
        • Article: not found

        K-ras mutations and benefit from cetuximab in advanced colorectal cancer.

        Treatment with cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, improves overall and progression-free survival and preserves the quality of life in patients with colorectal cancer that has not responded to chemotherapy. The mutation status of the K-ras gene in the tumor may affect the response to cetuximab and have treatment-independent prognostic value. We analyzed tumor samples, obtained from 394 of 572 patients (68.9%) with colorectal cancer who were randomly assigned to receive cetuximab plus best supportive care or best supportive care alone, to look for activating mutations in exon 2 of the K-ras gene. We assessed whether the mutation status of the K-ras gene was associated with survival in the cetuximab and supportive-care groups. Of the tumors evaluated for K-ras mutations, 42.3% had at least one mutation in exon 2 of the gene. The effectiveness of cetuximab was significantly associated with K-ras mutation status (P=0.01 and P<0.001 for the interaction of K-ras mutation status with overall survival and progression-free survival, respectively). In patients with wild-type K-ras tumors, treatment with cetuximab as compared with supportive care alone significantly improved overall survival (median, 9.5 vs. 4.8 months; hazard ratio for death, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001) and progression-free survival (median, 3.7 months vs. 1.9 months; hazard ratio for progression or death, 0.40; 95% CI, 0.30 to 0.54; P<0.001). Among patients with mutated K-ras tumors, there was no significant difference between those who were treated with cetuximab and those who received supportive care alone with respect to overall survival (hazard ratio, 0.98; P=0.89) or progression-free survival (hazard ratio, 0.99; P=0.96). In the group of patients receiving best supportive care alone, the mutation status of the K-ras gene was not significantly associated with overall survival (hazard ratio for death, 1.01; P=0.97). Patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab, whereas patients with a tumor bearing wild-type K-ras did benefit from cetuximab. The mutation status of the K-ras gene had no influence on survival among patients treated with best supportive care alone. (ClinicalTrials.gov number, NCT00079066.) 2008 Massachusetts Medical Society
          Bookmark
          • Record: found
          • Abstract: found
          • Article: not found

          Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.

          Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P < .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.
            Bookmark

            Author and article information

            Affiliations
            [1 ]Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland
            [2 ]Swim Across America Laboratory at Johns Hopkins, Baltimore, Maryland
            [3 ]Amgen Inc., Thousand Oaks, California
            [4 ]State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, The Fourth Military Medical University, Xi’an, P. R. China
            [5 ]Division of Hematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, California
            [6 ]Vanderbilt University Medical Center, Nashville, Tennessee
            [7 ]Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts
            [8 ]IST Austria (Institute of Science and Technology Austria), Klosterneuburg, Austria
            Author notes
            []To whom correspondence should be addressed. ldiaz1@ 123456jhmi.edu (Luis Diaz) and koliner@ 123456amgen.com (Kelly Oliner)
            Journal
            0410462
            6011
            Nature
            Nature
            Nature
            0028-0836
            1476-4687
            31 May 2012
            28 June 2012
            28 December 2012
            : 486
            : 7404
            : 537-540
            22722843 3436069 10.1038/nature11219 NIHMS376108

            Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

            Funding
            Funded by: National Cancer Institute : NCI
            Award ID: P50 CA095103 || CA
            Funded by: National Cancer Institute : NCI
            Award ID: P50 CA095103 || CA
            Funded by: National Cancer Institute : NCI
            Award ID: P50 CA095103 || CA
            Funded by: National Cancer Institute : NCI
            Award ID: P50 CA095103 || CA
            Funded by: National Cancer Institute : NCI
            Award ID: P50 CA095103 || CA
            Funded by: National Cancer Institute : NCI
            Award ID: P50 CA095103 || CA
            Funded by: National Cancer Institute : NCI
            Award ID: P50 CA095103 || CA
            Funded by: National Cancer Institute : NCI
            Award ID: P50 CA095103 || CA
            Funded by: National Cancer Institute : NCI
            Award ID: P50 CA095103 || CA
            Funded by: National Cancer Institute : NCI
            Award ID: P50 CA095103 || CA
            Funded by: National Cancer Institute : NCI
            Award ID: P50 CA095103 || CA
            Categories
            Article

            Uncategorized

            Comments

            Comment on this article