Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Are RAS mutations predictive markers of resistance to standard chemotherapy?

Nature Reviews Clinical Oncology volume 6, pages 528–534 (2009)Cite this article

Abstract

KRAS mutations may be predictive of resistance to anti-EGFR monoclonal-based therapy in patients with colorectal cancer (CRC). Screening for KRAS mutations in patients with CRC and non-small-cell lung cancer (NSCLC) may provide additional information on optimizing treatment options with targeted therapies. Only limited studies, however, have assessed the predictive value of KRAS mutations in response to conventional chemotherapy. We reviewed all relevant papers investigating the association of KRAS mutations and conventional chemotherapy-related outcome in NSCLC, CRC, and other solid tumors, both in the adjuvant and advanced settings. Our Review strongly suggests that KRAS mutations have no value in response prediction to conventional chemotherapy in NSCLC, CRC and other solid tumors. Therefore, KRAS mutations should not be used as molecular predictors of response to conventional chemotherapy.

Key Points

  • Activating RAS mutations occur in 30% of human cancers and are the most common gain-of-function mutations

  • KRAS mutations are molecular predictors for the lack of benefit of anti-EGFR monoclonal-based therapy in colorectal cancer

  • In lung cancer, colorectal cancer, and other solid tumors, KRAS mutations have no value for predicting response to conventional chemotherapy

  • KRAS mutations should not be used within the decision algorithm of chemotherapy

  • All these findings need to be confirmed in prospective trials with appropriate multivariate analysis taking into account other clinical and biological predictors

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Schubbert, S., Shannon, K. & Bollag, G. Hyperactive Ras in developmental disorders and cancer. Nat. Rev. Cancer 7, 295–308 (2007).

    Article  CAS  Google Scholar 

  2. Rodenhuis, S. et al. Mutational activation of the K-ras oncogene and the effect of chemotherapy in advanced adenocarcinoma of the lung: a prospective study. J. Clin. Oncol. 15, 285–291 (1997).

    Article  CAS  Google Scholar 

  3. Marks, J. L. et al. Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma. J. Thorac. Oncol. 3, 111–116 (2008).

    Article  Google Scholar 

  4. Mascaux, C. et al. The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br. J. Cancer 92, 131–139 (2005).

    Article  CAS  Google Scholar 

  5. Eberhard, D. A. et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J. Clin. Oncol. 23, 5900–5909 (2005).

    Article  CAS  Google Scholar 

  6. Lievre, A. et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66, 3992–3995 (2006).

    Article  CAS  Google Scholar 

  7. Di Fiore, F. et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br. J. Cancer 96, 1166–1169 (2007).

    Article  CAS  Google Scholar 

  8. Karapetis, C. S. et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 359, 1757–1765 (2008).

    Article  CAS  Google Scholar 

  9. Amado, R. G. et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 1626–1634 (2008).

    Article  CAS  Google Scholar 

  10. Tsai, C. M. et al. Correlation of intrinsic chemoresistance of non-small-cell lung cancer cell lines with HER-2/neu gene expression but not with ras gene mutations. J. Natl Cancer Inst. 85, 897–901 (1993).

    Article  CAS  Google Scholar 

  11. Kelland, L. The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer 7, 573–584 (2007).

    Article  CAS  Google Scholar 

  12. Chin, K. V., Ueda, K., Pastan, I. & Gottesman, M. M. Modulation of activity of the promoter of the human MDR1 gene by Ras and p53. Science 255, 459–462 (1992).

    Article  CAS  Google Scholar 

  13. Wishart, G. C., Plumb, J. A., Spandidos, D. A. & Kerr, D. J. H-ras infection in mink lung epithelial cells may induce 'atypical' multidrug resistance. Eur. J. Cancer 27, 673 (1991).

    Article  CAS  Google Scholar 

  14. Yagüe, E. et al. Ability to acquire drug resistance arises early during the tumorigenesis process. Cancer Res. 67, 1130–1137 (2007).

    Article  Google Scholar 

  15. Schmidt, C. J. & Hamer, D. H. Cell specificity and an effect of ras on human metallothionein gene expression. Proc. Natl Acad. Sci. USA 83, 3346–3350 (1986).

    Article  CAS  Google Scholar 

  16. Isonishi, S. et al. Expression of the c-Ha-RAS oncogene in mouse NIH 3T3 cells induces resistance to cisplatin. Cancer Res. 51, 5903–5909 (1991).

    CAS  PubMed  Google Scholar 

  17. Niimi, S. et al. Resistance to anticancer drugs in NIH3T3 cells transfected with c-myc and/or c-H-ras genes. Br. J. Cancer 63, 237–241 (1991).

    Article  CAS  Google Scholar 

  18. Merkel, P., Khoury, N., Bertolotto, C. & Perfetti, R. Insulin and glucose regulate the expression of the DNA repair enzyme XPD. Mol. Cell. Endocrinol. 201, 75–85 (2003).

    Article  CAS  Google Scholar 

  19. Lee-Kwon, W., Park, D. & Bernier, M. Involvement of the Ras/extracellular signal-regulated kinase signalling pathway in the regulation of ERCC-1 mRNA levels by insulin. Biochem. J. 331, 591–597 (1998).

    Article  CAS  Google Scholar 

  20. Mabry, M. et al. v-Ha-ras oncogene insertion: a model for tumor progression of human small cell lung cancer. Proc. Natl Acad. Sci. USA 85, 6523–6527 (1988).

    Article  CAS  Google Scholar 

  21. Kaufmann, S. H., Kalemkerian, G. P., Jasti, R. & Mabry, M. Effect of v-rasH on sensitivity of NCI-H82 human small cell lung cancer cells to cisplatin, etoposide, and camptothecin. Biochem. Pharmacol. 50, 1987–1993 (1995).

    Article  CAS  Google Scholar 

  22. Rosell, R. et al. Mutated K-ras gene analysis in a randomized trial of preoperative chemotherapy plus surgery versus surgery in stage IIIA non-small cell lung cancer. Lung Cancer 12 (Suppl. 1), S59–S70 (1995).

    Article  Google Scholar 

  23. Schiller, J. H. et al. Lack of prognostic significance of p53 and K-ras mutations in primary resected non-small-cell lung cancer on E4592: a Laboratory Ancillary Study on an Eastern Cooperative Oncology Group Prospective Randomized Trial of Postoperative Adjuvant Therapy. J. Clin. Oncol. 19, 448–457 (2001).

    Article  CAS  Google Scholar 

  24. Tsao, M. S. et al. Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non small-cell lung cancer. J. Clin. Oncol. 25, 5240–5247 (2007).

    Article  Google Scholar 

  25. Zalcman, G. et al. Use of RAS effector RASSF1A promoter gene methylation and chromosome 9p loss of heterozygosity (LOH) to predict progression-free survival (PFS) in perioperative chemotherapy (CT) phase III trial IFCT-0002 in resectable non-small cell lung cancer [abstract]. ASCO Meeting Abstracts 26, 7500 (2008).

    Google Scholar 

  26. Longley, D. B., Harkin, D. P. & Johnston, P. G. 5-fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer 3, 330–338 (2003).

    Article  CAS  Google Scholar 

  27. Klampfer, L. et al. Oncogenic Ras increases sensitivity of colon cancer cells to 5-FU-induced apoptosis. Oncogene 24, 3932–3941 (2005).

    Article  CAS  Google Scholar 

  28. Agarwal, B. et al. Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells. Clin. Cancer Res. 5, 2223–2239 (1999).

    CAS  PubMed  Google Scholar 

  29. Tseng, Y. S. et al. Ha-ras overexpression mediated cell apoptosis in the presence of 5-fluorouracil. Exp. Cell Res. 288, 403–414 (2003).

    Article  CAS  Google Scholar 

  30. Huang, Y., Horvath, C. M. & Waxman, S. Regrowth of 5-fluorouracil-treated human colon cancer cells is prevented by the combination of interferon gamma, indomethacin, and phenylbutyrate. Cancer Res. 60, 3200–3206 (2000).

    CAS  PubMed  Google Scholar 

  31. Houghton, J. A., Ebanks, R., Harwood, F. G. & Tillman, D. M. Inhibition of apoptosis after thymineless stress is conferred by oncogenic K-Ras in colon carcinoma cells. Clin. Cancer Res. 4, 2841–2848 (1998).

    CAS  PubMed  Google Scholar 

  32. Scanlon, K. I. et al. Ribozyme-mediated cleavage of c-fos mRNA reduces gene expression of DNA synthesis enzymes and metallothionein. Proc. Natl Acad. Sci. USA 88, 10591–10595 (1991).

    Article  CAS  Google Scholar 

  33. Giovanella, B. C. et al. DNA topoisomerase I—targeted chemotherapy of human colon cancer in xenografts. Science 246, 1046–1048 (1989).

    Article  CAS  Google Scholar 

  34. Markowitz, S. et al. Mutant K-ras oncogenes in colon cancers do not predict patient's chemotherapy response or survival. Clin. Cancer Res. 1, 441–445 (1995).

    CAS  PubMed  Google Scholar 

  35. Bleeker, W. A. et al. Prognostic significance of K-ras and TP53 mutations in the role of adjuvant chemotherapy on survival in patients with Dukes C colon cancer. Dis. Colon Rectum 44, 358–363 (2001).

    Article  CAS  Google Scholar 

  36. Ahnen, D. J. et al. Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: a Southwest Oncology Group study. Cancer Res. 58, 1149–1158 (1998).

    CAS  PubMed  Google Scholar 

  37. Westra, J. L. et al. Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients. J. Clin. Oncol. 23, 5635–5643 (2005).

    Article  CAS  Google Scholar 

  38. Etienne-Grimaldi, M. C. et al. K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy. Clin. Cancer Res. 14, 4830–4835 (2008).

    Article  CAS  Google Scholar 

  39. Nemunaitis, J., Cox, J., Meyer, W., Courtney, A. & Mues, G. Irinotecan hydrochloride (CPT-11) resistance identified by K-ras mutation in patients with progressive colon cancer after treatment with 5-fluorouracil (5-FU). Am. J. Clin. Oncol. 20, 527–529 (1997).

    Article  CAS  Google Scholar 

  40. Gnanasampanthan, G., Elsaleh, H., McCaul, K. & Iacopetta, B. Ki-RAS mutation type and the survival benefit from adjuvant chemotherapy in Dukes' C colorectal cancer. J. Pathol. 195, 543–548 (2001).

    Article  CAS  Google Scholar 

  41. Van Cutsem, E. et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408–1417 (2009).

    Article  CAS  Google Scholar 

  42. Bokemeyer, C. et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience [abstract]. ASCO Meeting Abstracts 26, 4000 (2008).

    Google Scholar 

  43. Gallagher, S. J. et al. p16INK4a expression and absence of activated B-RAF are independent predictors of chemosensitivity in melanoma tumors. Neoplasia 10, 1231–1239 (2008).

    Article  CAS  Google Scholar 

  44. Dergham, S. T., Dugan, M. C., Sarkar, F. H. & Vaitkevicius, V. K. Molecular alterations associated with improved survival in pancreatic cancer patients treated with radiation or chemotherapy. J. Hepatobiliary Pancreat. Surg. 5, 269–272 (1998).

    Article  CAS  Google Scholar 

  45. Bissada, E. et al. Prevalence of KRAS codon 12 mutations in locally advanced head and neck squamous cell carcinoma and influence with regards to response to chemoradiation therapy [abstract]. ASCO Meeting Abstracts 26, 17005 (2008).

    Google Scholar 

  46. Hachisuga, T. et al. K-ras mutation in the endometrium of tamoxifen-treated breast cancer patients, with a comparison of tamoxifen and toremifene. Br. J. Cancer. 92, 1098–1103 (2005).

    Article  CAS  Google Scholar 

  47. Wallén, M., Tomás, E., Visakorpi, T., Holli, K. & Mäenpää, J. Endometrial K-ras mutations in postmenopausal breast cancer patients treated with adjuvant tamoxifen or toremifene. Cancer Chemother. Pharmacol. 55, 343–346 (2005).

    Article  Google Scholar 

  48. Wistuba, I. I. & Gazdar, A. F. Gallbladder cancer: lessons from a rare tumour. Nat. Rev. Cancer 4, 695–706 (2004).

    Article  CAS  Google Scholar 

  49. Verslype, C., Prenen, H. & Van Cutsem, E. The role of chemotherapy in biliary tract carcinoma. HPB (Oxford) 10, 164–167 (2008).

    Article  CAS  Google Scholar 

  50. Ince, W. L. et al. Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J. Natl Cancer Inst. 97, 981–989 (2005).

    Article  CAS  Google Scholar 

  51. Rosty, C. et al. Determination of microsatellite instability, p53 and K-RAS mutations in hepatic metastases from patients with colorectal cancer: relationship with response to 5-fluorouracil and survival. Int. J. Cancer 95, 162–167 (2001).

    Article  CAS  Google Scholar 

  52. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 69, 89–95 (2001).

  53. Michiels, S., Koscielny, S. & Hill, C. Interpretation of microarray data in cancer. Br. J. Cancer 96, 1155–1158 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank H. Lord for her help in editing the manuscript. Y. Loriot and P. Mordant contributed equally to this article.

Author information

Authors and Affiliations

  1. Department of Medicine, SITEP, University Paris XI, Institut Gustave Roussy, Villejuif, France

    Yohann Loriot & Jean-Charles Soria

  2. UPRES 2710, University Paris XI, Institut Gustave Roussy, Villejuif, France

    Pierre Mordant & Eric Deutsch

  3. Translational Research Laboratory, University Paris XI, Institut Gustave Roussy, Villejuif, France

    Ken André Olaussen

Authors
  1. Yohann Loriot
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pierre Mordant
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eric Deutsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ken André Olaussen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jean-Charles Soria
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jean-Charles Soria.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Loriot, Y., Mordant, P., Deutsch, E. et al. Are RAS mutations predictive markers of resistance to standard chemotherapy?. Nat Rev Clin Oncol 6, 528–534 (2009). https://doi.org/10.1038/nrclinonc.2009.106

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2009.106

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing