Chapter 080. Cancer Cell Biology and Angiogenesis (Part 6)

Imatinib has also demonstrated targeted activity in other diseases, including gastrointestinal stromal tumors (GIST), rare mesenchymal tumors of the GI tract (stomach and small intestine). The pathogenic molecular event for most patients with this disease is mutation of the proto-oncogene c-Kit, leading to the constitutive activation of this receptor tyrosine kinase without the binding of its physiologic ligand, stem cell factor. About 10% of GISTs encode activating mutations of the PDGFRα instead of c-Kit. GISTs are thought to arise from or share a common stem cell with the interstitial cells of Cajal, which give rise to the myenteric plexus...
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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 6) Chapter 080. Cancer Cell Biology and Angiogenesis (Part 6) Imatinib has also demonstrated targeted activity in other diseases, includinggastrointestinal stromal tumors (GIST), rare mesenchymal tumors of the GI tract(stomach and small intestine). The pathogenic molecular event for most patientswith this disease is mutation of the proto-oncogene c-Kit, leading to theconstitutive activation of this receptor tyrosine kinase without the binding of itsphysiologic ligand, stem cell factor. About 10% of GISTs encode activatingmutations of the PDGFRα instead of c-Kit. GISTs are thought to arise from orshare a common stem cell with the interstitial cells of Cajal, which give rise to themyenteric plexus of the GI tract. Imatinib, which inhibits the c-Kit kinase domain,has demonstrated significant activity (>50% partial responses usually lasting 1–2years) in this chemotherapy-refractory tumor. Resistance to imatinib develops dueto secondary mutations in c-Kit, and many of these tumors are susceptible totreatment with the multitargeted TK inhibitor sunitinib that has activity against c-Kit as well as the PDGF and vascular endothelial growth factor (VEGF) receptors.Sunitinib is approved by the U.S. Food and Drug Administration for treatment ofpatients with imatinib-resistant GIST or who are intolerant of imatinib (Table 80-2). Interestingly, tumors with mutations in exon 11 of c-Kits juxtamembraneregion are particularly sensitive to imatinib, whereas those with exon 9 mutations(extracellular domain) respond better to sunitinib than imatinib. In the future,primary therapy for GIST may be determined by the specific molecular defect inc-Kit. Patients with chronic myelomonocytic leukemia (CMML, amyeloproliferative disorder) often harbor a Tel-PDGFR translocation that resultsin constitutive activation of the PDGFR kinase domain exclusively in the leukemiccells. Imatinib inhibits this kinase and has demonstrated significant activity in thisdisease. These examples extend the proof of principle that targeting of signalingpathways in cancer cells can be highly efficacious with minimal toxicity, evenwhen the drug does not have absolute target specificity. Imatinib has become theparadigm of targeted drug development in other diseases. Targeting Other Receptor Tyrosine Kinases Epidermal growth factor receptor (EGFR) mutations define a novel subsetof lung cancers. Clinical studies of two high-affinity competitive inhibitors of theATP binding site in the EGFR kinase domain, gefitinib and erlotinib, haveprovided important insights into the pathogenesis of different subsets of patientswith non-small cell lung cancer (NSCLC). Phase III studies led to FDA approvalafter ~10–20% of advanced-stage patients treated with single-agent gefitinib orerlotinib had objective tumor responses. Responders tended to haveadenocarcinoma or bronchoalveolar histology (not squamous or large cell), andwere never-smokers, women, and of Eastern Asian origin. DNA sequence analysisof the EGFR gene isolated from the tumors of responding patients (mostlynonsmokers) demonstrated that most had acquired mutations of the kinase domainthat led to increased tyrosine kinase activity. Frequently, patients with mutatedalleles also had evidence of EGFR gene amplification by fluorescence in situhybridization (FISH). These tumors exhibited euploid chromosome content, incontrast to tumors from smokers, which were most often aneuploid and harboredmutations in the K-Ras oncogene. In fact, mutated K-Ras, which occurs to theexclusion of EGFR mutation, appears to define a subset of patients with lowlikelihood of response to EGFR inhibitors. Thus the model has been proposed thatthe pathogenesis of NSCLC in never-smokers occurs through a novel pathway thatis dependent on activated EGFR, and that tumors are addicted to this oncogene,rendering them highly susceptible to its inhibition (see Fig. 80-7). No EGFRkinase domain mutations have yet been found in tumors other than NSCLC. Thus,these studies define a novel oncogenic pathway for an important human cancer,and provide a mechanism to identify subsets of patients likely to respond to thetargeted therapy. The wild-type EGFR is expressed by many other human cancers,and in colon cancer and head and neck cancers, targeting of the EGFR with amonoclonal antibody (cetuximab) has demonstrated improved survival whencombined with chemotherapy or radiation therapy. HER2/neu is a target in human breast cancer. The gene encodingHER2/neu, a member of the EGFR family, is amplified in ~20% of breast cancers.Tumors that overexpress HER2/neu are less responsive to chemotherapy, andpatients wi ...