EGFR inhibitors

Many therapeutic approaches are aimed at epidermal growth factor receptor (EGFR). Cetuximab and panitumumab are examples of monoclonal antibody inhibitors. However the former is of the IgG1 type, the latter of the IgG2 type; consequences on antibody-dependent cellular cytotoxicity can be quite different.[1] Other monoclonals in clinical development are zalutumumab, nimotuzumab, and matuzumab. The monoclonal antibodies block the extracellular ligand binding domain. With the binding site blocked, signal molecules can no longer attach there and activate the tyrosine kinase.

Another method is using small molecules to inhibit the EGFR tyrosine kinase, which is on the cytoplasmic side of the receptor. Without kinase activity, EGFR is unable to activate itself, which is a prerequisite for binding of downstream adaptor proteins. Ostensibly by halting the signaling cascade in cells that rely on this pathway for growth, tumor proliferation and migration is diminished. Gefitinib, erlotinib, and lapatinib (mixed EGFR and ERBB2 inhibitor) are examples of small molecule kinase inhibitors.

There are several quantitative methods available that use protein phosphorylation detection to identify EGFR family inhibitors.[2]

New drugs such as gefitinib and erlotinib directly target the EGFR. Patients have been divided into EGFR-positive and EGFR-negative, based upon whether a tissue test shows a mutation. EGFR-positive patients have shown a 60% response rate, which exceeds the response rate for conventional chemotherapy.[3]

However, many patients develop resistance. Two primary sources of resistance are the T790M mutation and MET oncogene.[3] However, as of 2010 there was no consensus of an accepted approach to combat resistance nor FDA approval of a specific combination. Preclinical results have been reported for AP26113 which targets the T790M mutation.

The most common adverse effect of EGFR inhibitors, found in more than 90% of patients, is a papulopustular rash that spreads across the face and torso; the rash's presence is correlated with the drug's antitumor effect.[4] In 10% to 15% of patients the effects can be serious and require treatment.[5][6]

References

  1. ↑ Yan L, Beckman RA (October 2005). "Pharmacogenetics and pharmacogenomics in oncology therapeutic antibody development". BioTechniques. 39 (4): 565–8. doi:10.2144/000112043. PMID 16235569.
  2. ↑ Olive DM (October 2004). "Quantitative methods for the analysis of protein phosphorylation in drug development". Expert Rev Proteomics. 1 (3): 327–41. doi:10.1586/14789450.1.3.327. PMID 15966829.
  3. 1 2 Jackman DM, Miller VA, Cioffredi LA, Yeap BY, Jänne PA, Riely GJ, Ruiz MG, Giaccone G, Sequist LV, Johnson BE (August 2009). "Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials". Clin. Cancer Res. 15 (16): 5267–73. doi:10.1158/1078-0432.CCR-09-0888. PMC 3219530Freely accessible. PMID 19671843.
  4. ↑ Liu HB, Wu Y, Lv TF, Yao YW, Xiao YY, Yuan DM, Song Y (2013). "Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: a systematic review and meta-analysis". PLoS ONE. 8 (1): e55128. doi:10.1371/journal.pone.0055128. PMC 3559430Freely accessible. PMID 23383079.
  5. ↑ Gerber PA, Meller S, Eames T, Buhren BA, Schrumpf H, Hetzer S, Ehmann LM, Budach W, Bölke E, Matuschek C, Wollenberg A, Homey B (2012). "Management of EGFR-inhibitor associated rash: a retrospective study in 49 patients". Eur. J. Med. Res. 17: 4. doi:10.1186/2047-783X-17-4. PMC 3351712Freely accessible. PMID 22472354.
  6. ↑ Lacouture ME (2006). "Mechanisms of cutaneous toxicities to EGFR inhibitors". Nat. Rev. Cancer. 6 (10): 803–12. doi:10.1038/nrc1970. PMID 16990857.


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