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Integrating molecular diagnostics into anticancer drug discovery

Nature Reviews Drug Discovery volume 9, pages 523–535 (2010)Cite this article

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Abstract

In the 1990s, the breast cancer drug trastuzumab (Herceptin; Genentech/Roche) — an antibody specific for human epidermal growth factor receptor 2 (HER2; also known as ERBB2) — was approved based on trials in which HER2 expression levels were used to select patients in clinical trials. This provided support for analogous efforts for drugs that target the epidermal growth factor receptor (EGFR). However, the development of these drugs, such as cetuximab (Erbitux; Bristol–Myers Squibb/Lilly) and gefitinib (Iressa; AstraZeneca), has revealed that EGFR expression is an insufficient and unreliable biomarker to select patients for EGFR-targeted therapies in both lung and colon cancer. Indeed, evidence on patient populations that are likely to respond to such therapies, on the basis of specific mutations in proteins of the targeted pathway, has only recently been clinically validated and incorporated into some of the drug labels. This article highlights lessons learned from the development of the first drugs targeting the EGFR family and discusses strategies to decrease the risk of failure in clinical development by more effectively integrating molecular diagnostics into anticancer drug discovery.

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Figure 1: Molecular mechanism of EGFR signal-dependence in epithelial cancers.
Figure 2: Prevalence of predictive biomarkers of response to EGFR inhibitors.
Figure 3: Personalized therapy for lung adenocarcinomas.
Figure 4: On-target approach in the clinical development and registration of anticancer signal transduction therapies.

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Acknowledgements

This work was supported by grants (KKKII-05/2005, NKFP_07_A2-NANODRUG, TECH_08_A2-STEMKILL, NAP_BIO_06-FLU_DRUG and OTKA-T046665).

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  1. and the Ist Department of Pathology and Experimental Cancer Research, István Peták is at KPS Medical Biotechnology and Healthcare Services Ltd, 5 Ribary, 1022 Budapest, Hungary, Semmelweis University, 26 Üllői út, 1085 Budapest, Hungary.,

    István Peták

  2. Richárd Schwab is at KPS Medical Biotechnology and Healthcare Services Ltd, 5 Ribary, 1022 Budapest, Hungary.,

    Richárd Schwab

  3. and the Department of Pharmaceutical Chemistry, László Őrfi is at Vichem Chemie Research Ltd, Budapest, Hungary, Semmelweis University, Högyes E. u. 9., 1092 Budapest, Hungary.,

    László Őrfi

  4. László Kopper is at the Ist Department of Pathology and Experimental Cancer Research, Semmelweis University, 26 Üllői út, 1085 Budapest, Hungary.,

    László Kopper

  5. Department of Medical Chemistry and Pathobiochemistry, György Kéri is at Vichem Chemie Research Ltd, Budapest, Hungary, and the Pathobiochemistry Research Group of the Hungarian Academy of Sciences, Semmelweis University, Budapest, H-1085, Hungary.,

    György Kéri

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  1. István Peták
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  2. Richárd Schwab
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  3. László Őrfi
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  4. László Kopper
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  5. György Kéri
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Correspondence to István Peták.

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Competing interests

István Peták and Richárd Schwab are co-founders of KPS, a company working in the field of molecular diagnostics. György Kéri and László Őrfi are co-founders of Vichem, a drug discovery company focusing on kinase inhibitors. István Peták and László Kopper have occasionally served on the advisory board of and have received honoraria from the Hungarian subsidies of Roche, AstraZeneca, Merck and Amgen.

Supplementary information

Supplementary information S1 (box)

Case study of an EGFR-TKI treated lung cancer patient (PDF 294 kb)

Supplementary information S2 (table)

Major clinical responses to signal transduction therapies are usually associated with the presence of cancer specific genetic changes detected by molecular diagnostic methods. (PDF 205 kb)

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Peták, I., Schwab, R., Őrfi, L. et al. Integrating molecular diagnostics into anticancer drug discovery. Nat Rev Drug Discov 9, 523–535 (2010). https://doi.org/10.1038/nrd3135

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