epidermal growth factor receptor as a target for cancer therapy
TRANSCRIPT
Editorial
10.1586/14737140.7.1.1 © 2007 Future Drugs Ltd ISSN 1473-7140 1
Epidermal growth factor receptor as a target for cancer therapy‘We are moving toward the era when the cancer treatment will be focused on the biological characteristics of cancer rather than generalized treatment.’
Ramin Altaha and Jame Abraham†
†Author for correspondenceMary Babb Randolph Cancer Center, West Virginia University, PO Box 9162, Morgantown, WV 26506, USATel.: +1 304 293 4229Fax: +1 304 293 [email protected]
Expert Rev. Anticancer Ther. 7(1), 1–3 (2007)
Epidermal growth factor (EGF) was identifiedin 1962, followed by purification of the EGFreceptor (EGFR) in 1980. Since then, over-expression of EGFR has been found to corre-late with the poor outcomes of cancer patients.In 1984, the human homolog of v-erb-b andc-erb-b (EGFR) was cloned and overexpressionwas shown to have transforming capacity. Atthe same time, the first monoclonal antibody(mAb) against EGFR, so-called ‘C225’, wassynthesized. This drug, which was named latercetuximab, was later approved for metastaticcolon cancer in 2004. Back in 1994, the firstEGFR tyrosine kinase inhibitor (TKI) wasidentified. The first drug from this class thatmade it to the market (gefitinib) was approvedin 2003 for second-line therapy for patientswith locally advanced/metastatic nonsmall celllung cancer. The rationale for EGFR as a targetfor anticancer development was based on over-expression of this marker in many tumors andalso low levels of expression in normal tissues.Overexpression of EFGR can transform cells ina ligand-dependent manner, it is frequentlydysregulated in carcinomas and it can initiatesignal transduction cascades that increasetumor cell proliferation, prevents tumor cellapoptosis and promotes distant metastasis. Thehuman epidermal growth factor (HER) familyof receptors incorporates four receptor types:HER1 (EGFR), HER2, HER3 and HER4.EGFR contains an extracellular ligand-bindingdomain, a transmembrane domain and anintracellular tyrosine kinase domain. Bindingof the growth factors or ligands induces confor-mational changes in the extracellular domain ofthe receptor that facilitates dimerization orclustering of receptor tyrosine kinases [1].
The proposed mechanism of action ofEGFR-targeted TKIs are through the blockadeof the ATP-binding site, which prevents theautophosporylation of the tyrosine kinasedomain of the receptor. Subsequently, the acti-vation of mitogen activated protein kinase andphosphoinositide-3 kinase are prevented, whichleads to cell-cycle arrest at G1 and apoptosis,respectively [2].
Gefitinib was approved by the US FDA as asecond-line treatment for nonsmall cell lungcancer based on two Phase II clinical trials,IDEAL 1 and 2 after platinum failure. A 10%antitumor activity was noted when gefitinib wasadministered after chemotherapy failure. How-ever, the Phase III clinical trials INTACT 1 and2 did not show any benefit compared with pla-cebo when gefitinib was administered concomi-tantly with chemotherapy. In a follow-up, PhaseIII clinical trial, the so-called ISEL-trial, gefit-inib was compared with best supportive care;gefitinib did not show any survival benefit com-pared with placebo. Based on these studies,AstraZeneca (Södertälje, Sweden) decided tohold further promotion of gefitinib, except forthe ongoing clinical trials.
However, considering the response rate of10%, similar to other second-line cytotoxicagents, with significantly less side effects, gefit-inib appeared to be a good alternative. Amongthose 10% of patients who responded to gefit-inib, there were patients with dramaticresponses, unheard of by any kind of standardcytotoxic chemotherapies. The question wasraised as to why there were such mixed results.Is this due to the antagonistic effect of chemo-therapy and gefitinib or our inability to selectan appropriate patient population.
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Altaha & Abraham
2 Expert Rev. Anticancer Ther. 7(1), (2007)
The second targeted drug that made it to market from theclass TKIs was erlotinib. Based on a Phase III clinical trial fromthe National Cancer Institute of Canada (BR.21), erlotinib wasapproved in advanced/metastatic nonsmall cell lung cancerpatients after platinum failure. Overall survival was improved by2 months compared with placebo, with a 27% risk reduction ofdeath. However, again the combination of this so-called smallmolecule with chemotherapy in two subsequent clinical trials,TALENT and TRIBUTE, showed no evidence of significantimprovement of overall survival compared with placebo.
In mid 2004, two groups simultane-ously published their data regardingnonsmall cell lung cancer patients whoresponded to gefitinib. They reportedthat patients who carry specific muta-tions in their tyrosine kinase domainexons 18, 19, 20 and 21 had significantresponse to TKI. In the study by Lynchand colleagues, eight out of ninepatients with the mutations hadresponse to gefitinib (89%) and in the study by Paez and col-leagues, seven out of ten patients had a response to the treat-ment with TKI (70%). Since then, many groups have retro-spectively reported mutational analysis on nonsmall cell lungcancer patients who responded to erlotinib or gefitinib. Therate of the mutations in these studies ranges from 65 to 90%.Asians, females and adenocarcinoma patients harbor more fre-quent EGFR tyrosine kinase mutations and are, therefore, thebest responders. More than 200 different mutations have beendetected in the tyrosine kinase domain of EGFR in patientswith nonsmall cell lung cancer; however, more than 90% ofthese mutations are in two specific locations; a deletion in exon19 and a point mutation at exon 21 [3–5].
Predictive tests for EGFR inhibitorsEGFR-protein immunohistochemistry is upregulated in 90%of lung cancers. The significance of this marker and response toEGFR inhibitors is controversial. EGFR gene copies are testedby PCR. EGFR gene amplification can be found in 20–40% oflung cancers and it is suggested that tumors containing EGFRgene amplification or high gene copies would benefit morefrom EGFR TKIs as a second-line approach.
EGFR tyrosine kinase mutations have been found in 13% ofthe US population and it appears that patients with tyrosinekinase mutations experience a dramatic response and they benefitsignificantly from EGFR TKIs during the course of their treat-ment. As mentioned previously, the wild-type EGFR may haveminimal sensitivity to TKIs; however, it appears that differentmutations may have different sensitivities to these drugs.
Rule of EGFR ligand-binding domain inhibitors in human cancerBinding of specific ligands (e.g., EGF, transforming growth fac-tor [TGF]-α) to EGFR activates the receptor and triggers signaltransduction cascades that stimulates cell proliferation. EGFR
is expressed in many normal epithelial tissues and in manyhuman cancers, including those of colon and rectal. Cetuxi-mab is an IgG1 mAb that binds to EGFR and its heterodim-ers with high infinity, which is one log higher than its naturalligand. Cetuximab competitively inhibits ligand bindings toEGFR, stimulates receptor internalization and also blocksreceptor dimerization, which leads to blockage of tyrosinekinase phosphorylation and subsequently signal transduc-tion. The US FDA approved cetuximab for colorectal cancerin February 2004 based on a study in patients with meta-
static colorectal cancer who no longerresponded to irinotecan alone or iri-notecan in combination with otherchemotherapy drugs; the combinationtreatment of cetuximab and irinote-can shrunk tumors in 23% of patientsand delayed tumor growth forapproximately 4.1 months. Inpatients who received cetuximabalone, the tumor response rate was
11% and tumor growth was delayed by 1.5 months. InMarch 2006, cetuximab also received approval by the USFDA for the treatment of head and neck cancer. In a rand-omized clinical trial of 424 patients using cetuximab in com-bination with radiation therapy, the survival time was 49 ver-sus 29.3 months compared with patients receiving radiationtherapy alone. In addition, delayed tumor growth wasobserved with the use of cetuximab and radiation comparedwith radiation alone. In a second trial of 103 patients withrecurrent or metastatic squamous cell cancer of the head andneck, cetuximab helped to shrink the patient’s tumor afterthe tumor no longer responded to platinum-based therapy,with a response rate of 10%. Commonly reported side effectsof cetuximab were infusion reaction (fever, chills), skin rash,fatigue, malaise and nausea.
Future direction of EGFR-targeting drugsWith regards to EGFR TKI, patient selection is the key. Inour opinion, the tumor DNA of patients with nonsmall-celllung should be screened for the mutations in the tyrosinekinase domain. This is important since using a TKI in con-junction with standard chemotherapy in patients who do notcarry a specific mutation may be harmful, rather than benefi-cial to patients. However, patients who carry mutations havedramatic response to TKIs either as a single agent or in com-bination with chemotherapy. This makes sense from patho-physiological stand point since TKIs are cytostatic agents andchemotherapy are cytotoxic, thus, when cancer cells are incycle arrest due to TKI, cytotoxic chemotherapy is not aseffective as expected. However, data show that in patients whocarry the mutation, there was a synergistic effect when thesetwo agents were combined concomitantly.
With regard to cetuximab, no data have shown that certaintypes of patients experience more benefit compared with others;the level of EGFR expression measured by immunohistochemistry
‘...EGFR tyrosine kinase mutations have been found in 13% of the US
population and it appears that patients with tyrosine kinase
mutations experience a dramatic response and they benefit
significantly from EGFR TKIs during the course of their treatment.’
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Epidermal growth factor receptor as a target for cancer therapy
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in tumor tissue appears to play no role in responders. However, itappears that the development of classical rash correlates withresponse to cetuximab.
Other agents of interest includes lapatinib, which is a dualTKI. It is potent, small-molecule inhibitor of the erbB1 anderbB2 tyrosine kinases. The inhibitory effects, althoughreversible, result in blockade of receptor-mediated activationand propagation of downstream signaling involved in regula-tion of cell proliferation and cell survival. This drug is testedin HER-2/neu overexpressing breast cancer patients and has
shown significant response and improvement in time toprogression in patients who are resistant to trastuzumab. Inaddition, the lower incidence of CNS metastatic disease inpatients who are treated with lapatinib is a very interestingclinical observation.
We are moving toward the era when the cancer treatment will befocused on the biological characteristics of cancer rather than gener-alized treatment. Each individual patient needs to be evaluated sepa-rately. Their targets need to be identified and certain appropriatedrugs need to be administered for that individual cancer patient.
References
1 Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J. Clin. Oncol. 20(Suppl.), S1– S13 (2002).
2 Moyer JD, Barbacci EG, Iwata KK et al. Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res. 57(21), 4838–4848 (1997).
3 Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350(21), 2129–2139 (2004).
4 Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304(5676), 1497–1500 (2004).
5 Pao W, Miller VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J. Clin. Oncol. 23(11), 2556–2568 (2005).
Affiliations
• Ramin Altaha, MD
Section of Hematology/Oncology, Assistant Professor of Medicine, Mary Babb Randolph Cancer Center, West Virginia University, PO Box 9162, Morgantown, WV 26506, USATel.: +1 304 293 4229Fax: +1 304 293 [email protected]
• Jame Abraham, MD, FACP
Chief, Section of Hematology/Oncology, Associate Professor of Medicine and Medical Director, Mary Babb Randolph Cancer Center, West Virginia University, PO Box 9162, Morgantown, WV 26506, USATel.: +1 304 293 4229Fax: +1 304 293 [email protected]
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