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Opportunities and Challenges in the Development of Kinase Inhibitor Therapy for Cancer

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Opportunities and Challenges in the Development of Kinase Inhibitor Therapy for Cancer Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Opportunities and challenges in the development of kinase inhibitor therapy for cancer Charles L. Sawyers1 Howard Hughes Medical Institute; Departments of Medicine, Molecular and Medical Pharmacology, and Urology; and Jonsson Cancer Center; David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA The success of the tyrosine kinase imatinib inhibitor notion of “kinase dependency” states in cancer cells and (Gleevec, STI571) in treating chronic myeloid leukemia the challenges inherent in recognizing these tumors in as well as other selected cancers has greatly increased the clinic. I also outline a general strategy for conducting optimism for the broader application of kinase inhibitor first-in-human, phase I clinical trials of kinase inhibitors therapy in cancer. To date, however, imatinib remains that includes molecular enrollment criteria and precise the only spectacularly successful example. Is it simply a biochemical and biological measures of drug action in matter of time before kinase inhibitors become more tumor cells so that subsequent decisions for clinical de- broadly useful? Or is chronic myeloid leukemia a unique velopment of a novel compound might be more in- disease that does not reflect the true genetic complexity formed. of other cancers? Here I address this question by sum- marizing the growing evidence that kinase inhibitor therapy works consistently and reliably against cancers Present clinical experience with kinase inhibitors in which the kinase drug target is constitutively acti- The imatinib story in CML vated by gene mutation. I also discuss the prospects for extending this concept more broadly—to other cancers Chronic myeloid leukemia (CML) is a myeloproliferative in which kinase pathways are activated directly by ki- disease caused by constitutive activation of the Abl ki- nase gene mutation or indirectly by loss of negative regu- nase, as a consequence of fusion to the Bcr gene (Sawyers latory proteins (i.e., phosphatases such as the PTEN tu- 1999). This fusion event, originally recognized as the mor suppressor). Finally, I give my perspective on how t(9,22) Philadelphia chromosome translocation, occurs future drug discovery and clinical trial design programs in a pluripotent hematopoietic stem cell and leads to in molecularly targeted therapy could be modified based clonal expansion over a period of many years. At the on present clinical experience with kinase inhibitors. time of diagnosis, patients typically have peripheral blood counts 10–20-fold higher than normal, with an es- 12 In May 2001, approval of the first tyrosine kinase in- timated 10 or greater tumor cells. Remarkably, most hibitor for the treatment of a human cancer (imatinib/ patients have relatively few symptoms despite this dra- Gleevec for chronic myeloid leukemia) was greeted with matic tumor burden, presumably because CML cells re- great optimism by the oncology community, with hopes tain the ability to differentiate and function essentially for successful extension of this approach to other malig- as normal hematopoietic cells. At the cytogenetic level, nancies. One year later, the failure of a second tyrosine the Philadelphia chromosome is the only abnormality kinase inhibitor (gefitinib/Iressa), when combined with present during the initial stages of the disease (termed chemotherapy, to show superiority to standard treat- the chronic phase), leading to the concept that CML may ment for lung cancer led to reservations about the prom- be a “one hit” disease caused by a single molecular ab- ise of kinase inhibitors as anticancer agents. This review normality. With time, however, the disease progresses is my perspective on where we stand. Building on my and is associated with the rather abrupt acquisition of experience with the development of imatinib for chronic additional cytogenetic abnormalities as well as defects in myeloid leukemia, I summarize why I believe some the differentiation program. This stage, known as the clinical trials with this class of drugs have succeeded blast crisis, resembles acute leukemia and is rapidly fa- whereas others have failed. Central to my thinking is the tal. Thus, a simple model for the molecular pathophysi- ology of CML is that the disease is initiated by expres- sion of the BCR–ABL fusion protein in a single hemato- poietic stem cell, followed by the acquisition, years later, 1E-MAIL [email protected]; FAX (310) 206-8502. Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/ of several second hits that mediate the transition to the gad.1152403. blast crisis. A detailed cataloging of these second hits has 2998 GENES & DEVELOPMENT 17:2998–3010 © 2003 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/03 $5.00; www.genesdev.org Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Kinase inhibitors in cancer not been reported, but the list includes several genes remarkably similar to data from murine cancer models broadly implicated in cancer such as p53 and the p16/ expressing inducible transgenes (Chin et al. 1999; ARF locus (Ahuja et al. 1989; Foti et al. 1991; Neubauer Felsher and Bishop 1999). These models provide genetic et al. 1993; Sill et al. 1995). proof that the initiating oncogenic event may be required Imatinib is a small molecule kinase inhibitor that re- for tumor maintenance even at the very latest stages of versibly competes with ATP for binding to the kinase disease. Because nearly all cancers are presumed to re- domain of its target proteins. Imatinib was originally iso- quire multiple mutations for initiation and progression, lated in a screen for inhibitors of the platelet-derived this result in blast crisis CML bodes well for extending growth factor receptor (PDGFR), then subsequently kinase inhibitor therapy more broadly (assuming, of found to have activity against the Abl and Kit kinases course, that the relevant initiating lesion can be identi- (Buchdunger et al. 1995; Druker et al. 1996). After a re- fied and targeted). markable series of preclinical and clinical studies, which have been detailed in other reviews (Druker 2002; Shah Other clinical successes with imatinib: targeting Kit and Sawyers 2003), imatinib was approved for the treat- and PDGFR ment of CML in May 2001. In patients in the chronic phase of the disease, response rates are extremely high. CML is somewhat unique among cancers in that the Peripheral blood counts return to normal in >90% of disease begins in a clinical stage caused by (presumably) patients, and 50%–70% have no evidence of the Phila- a single molecular abnormality. Therefore, the success- delphia chromosome translocation in their bone marrow ful application of kinase inhibitor therapy in this setting after 3–6 mo of therapy, indicative of a 2–3 log reduction might be considered a special case. Convincing evidence in tumor burden. Subsequent studies using PCR to mea- that the paradigm of kinase inhibitor therapy can be ex- sure disease burden indicate that nearly all patients still tended more broadly requires clinical success in other have residual BCR–ABL-expressing cells in the blood cancers. Over the past two years, several examples have (Branford et al. 2002). Although the clinical significance fulfilled this promise. Gastrointestinal stromal tumors of this finding is unknown at present, it raises the pos- (GIST) are mesenchymal tumors of the stomach and sibility that imatinib alone is not curative therapy. Par- small intestine (formerly subclassified histologically allel studies of CML patients treated in the blast crisis with leiomyosarcomas) that arise from the intestinal indicated that imatinib also had impressive activity in cells of Cajal (Sircar et al. 1999). Unlike most sarcomas, late-stage disease, albeit short-lived because of rapid these tumors express the c-kit tyrosine kinase receptor. emergence of drug-resistant cells (Druker et al. 2001a; A significant fraction contain activating point mutations Sawyers et al. 2002). in the juxtamembrane or kinase domain of c-Kit that These clinical responses in blast crisis patients are par- lead to constitutive kinase activity (Hirota et al. 1998). ticularly interesting because they serve as proof of the Furthermore, mice engineered to express such activating concept that pharmacologic targeting of a single molecu- kit mutations in the germ line develop tumors that bear lar lesion can induce responses in cancers with multiple remarkable histologic similarity to human GISTs (Som- genetic abnormalities. Further evidence comes from mer et al. 2003). Based on these molecular findings from studies that have defined the mechanism of resistance to GIST tumors and the known inhibitory activity of ima- imatinib, which is caused predominantly by mutations tinib against c-kit in vitro, clinical studies of imatinib in BCR–ABL that prevent the drug from binding to the were initiated for GIST patients. Again, beneficial effects kinase domain (Gorre et al. 2001; Shah et al. 2002; Bran- were quickly apparent, because a large fraction of pa- ford et al. 2003). Thus, sustained kinase activation tients had complete or partial remissions (van Oosterom through BCR–ABL appears to be the Achilles’ heel of et al. 2001; Demetri et al. 2002). One particularly intrigu- CML even in the setting of a bewildering array of other ing feature of these responses is the utility of positron oncogene and tumor suppressor gene abnormalities. Re- emission tomography (PET) scanning using the tracer cent data suggest that these BCR–ABL mutations predate fluorodeoxyglucose. Prior to treatment, GIST tumors the initiation of imatinib treatment and presumably re- show avid fluorodeoxyglucose uptake, which is substan- flect mistakes in DNA replication that occur during ex- tially reduced after starting imatinib in patients, well in pansion of the tumor over years. In some cases, the mu- advance of tumor shrinkage based on CT scans (Joensuu tant clone has undergone tremendous clonal expansion et al.
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