Gnome writes "Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, the leading cause of death due to cancer. A growth factor (TGF-alpha) is thought to promote NSCLC proliferation through binding to the epidermal growth factor receptor (EGFR), which is found at high levels on the tumor cell surface. A competitive inhibitor of EGFR, gefitinib (trade name “Iressa”), failed in clinical trials but physicians reported dramatic improvement in ~10% of patients. Surprisingly, further investigation revealed that these patients’ tumors nearly all carried mutations around the ATP-binding site of EGFR, precisely the target of the drug. Several different mutations were detected. [This contrasts with a similar drug imatinib (STI-571, Gleevec), where mutations or amplifications of the target kinase reduce drug efficacy against leukemias (CML)]. Unfortunately, the benefit of gefitinib is transient (average 7 months) because additional EGFR mutations arise. Here, Kwak and colleagues show that gefitinib-resistant mutants are sensitive to non-competitive (irreversible) EGFR inhibitors named HKI-272, HKI-357, and EKB-569. These inhibitors alter the movement of EGFR in the cell. Although these studies must be extended to animals, targeting several pathways is well established, successful strategy in anti-viral treatment.
Kwak et al. PNAS 102:7665 (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib"
Saturday, November 25, 2006
Multi-pathway cancer inhibition
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Genetic Tests for Patients
Overactive kinases (phosphorylating enzymes) are associated with several cancers. STAT3, a kinase substrate, is overly active in several cancers including NSCLC. STAT3 normally cycles between phosphorylated/activated and dephosphorylated/inactivated. In the lab, STAT3 can be mutated and made permanently activated but no STAT3 mutations have been found in cancers. Instead, regulatory proteins such as PIAS (protein inhibitors of activated STAT) or SOCS (suppressor of cytokines signalling) are missing or inactive.
Chiarle and colleagues have shown that a tyrosine kinase that activates STAT3, ALK kinase, is itself persistently activated in a human lymphoma [nih.gov]. ALK is overexpressed in these tumor cells because of a chromosomal translocation (mutation) that joins the ALK gene to the (constitutively active?) nucleoplasmin gene, producing a NMP-ALK oncogene.
Genetic Tests for Patients
According to this news article from last August, 2 companies are selling screening test for patients who are candidates for Iressa [sciencemag.org]. One of the companies, with physicians from Massachusettes General Hospital, analyze the region of EGFR they previously showed is often mutated in responding patients. They wish to distribute the test to other hospitals instead of processing samples themselves. A second group from the City of Hope screen the entire EGFR gene on the grounds that some mutations lie outside ATP binding domain.
Mechanism of Aktion
James H. Doroshow has written an overview of the new NCIC (Canada) trial of gefitinib [nejm.org], the full findings just published in NEJM. He calls attention to 2 recent publications that add complexity to the mechanism of therapeutic effect. One finds ErbB3-mediated phosphatidyl-3-kinase activity in gefitinib-sensitive tumors [pnas.org]. The other finds that patients with amplified EGFR genes [oxfordjournals.org] were 10x more likely to respond and those with activated Akt (phosphorylated Akt, determined by immunohistochemistry) responded significantly better.
Off target inhibition
"The active sites of 491 human protein kinase domains are highly conserved" [nih.gov], quoting a May Science paper by Cohen et all [sic]. They characterize the design of selective inhibitors as "a formidable challenge". Indeed, different kinases could have identical sites but function in different pathways only because they are localized in different compartments.
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