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Polyclonal Resistance in Gastrointestinal Stromal Tumor Treated with Sequential Kinase Inhibitors

Royal Group of Hospitals, Belfast, United Kindom

Paul M. Waring

Genentech Inc., South San Francisco, CA

Alex Dobrovic

Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia

George Demetri

Director, Center for Sarcoma and Bone Oncology and the Ludwig Center for Cancer Research at Dana-Farber/Harvard Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

Serge Kovalenko

Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia

Grant McArthur

Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Department of Medicine St. Vincent's Hospital, The University of Melbourne, Parkville, Australia

To the Editor: We read with interest the article by Wardelmann et al. (1) describing the evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors (GIST) associated with resistance to treatment with imatinib mesylate. We have witnessed a similar emergence of multiple secondary KIT mutations conferring "polyclonal resistance" in a patient with GIST treated with imatinib and subsequently with the newer multi-targeted kinase inhibitor sunitinib malate (Pfizer, La Jolla, CA), which inhibits VEGFR1, VEGFR2, VEGFR3, PDGFR, and PDGFRß in addition to KIT.

A 51-year-old female with a duodenal GIST metastatic to the liver was treated with 400 mg of imatinib orally once daily. After a partial response lasting 14 months, she developed progressive disease while continuing imatinib and underwent debulking surgery. She was then enrolled on a trial evaluating sunitinib in imatinib-resistant GISTs. Follow-up with serial computed tomography measured five intra-abdominal tumors that were all defined as measurable index lesions using conventional methodology (Response Evaluation Criteria in Solid Tumors). There was a transient period of disease stability, which lasted 2 months, before progression of the largest index lesions and ensuing death. An autopsy with consent revealed extensive tumor throughout the peritoneal cavity in addition to terminal pulmonary embolism. Sequencing of KIT exons 9, 11, 13, and 17 was done on tumor samples from three different stages of disease, including a total of eight samples from the five index lesions sampled at autopsy (Fig. 1 ).

View larger version (13K): [in this window] [in a new window]   Fig. 1. Schematic diagram representing five intra-abdominal GIST index lesions and their KIT mutational profiles in a patient who was treated with imatinib and subsequently SU011248, was followed up with serial computed tomography while on SU011248, and who underwent autopsy examination. Lesion A, top right quadrant; lesion B, bottom right quadrant; lesion C, central pelvis; lesion D, within residual liver tissue (previous partial hepatectomy); lesion E, left anterior abdominal wall. Only the three largest lesions (A-C) increased in size on sunitinib. A primary KIT exon 11 del569_574 mutation was identified in all samples tested, and one of two secondary KIT kinase domain mutations (V654A or DH186) was identified in samples from three progressive tumors (A-C). Two samples tested from lesion B showed different mutational profiles. The two smallest index lesions (D and E) harbored no secondary KIT mutations and were nonprogressive on imaging.

The most common cause of imatinib resistance in GIST is the acquisition of secondary KIT mutations involving kinase domain I or II (exon 13, 14, or 17; refs. 1–3). This case shows with radiological, autopsy, and molecular correlation the emergence of multiple progressive GIST tumor clones from within a background of controlled disease, caused by the acquisition of secondary KIT kinase domain mutations. Such "polyclonal resistance" to imatinib has been previously described by Shah et al. in patients with chronic myeloid leukemia (4). In our case, sunitinib therapy initiated after the onset of imatinib resistance produced only limited benefit. The transient clinical response to sunitinib and the relative infrequency of the secondary D816H mutation within autopsy samples suggests that the D816H mutation may retain some sensitivity to inhibition by sunitinib, but the emergence of the sunitinib-resistant V654A mutation was associated with further disease progression and ultimately death.

The complexity of KIT mutational profiles in imatinib-resistant GIST makes it unlikely any single next-generation kinase inhibitor will effectively inhibit all mutant clones. However, the limited number of different mutations that are associated with imatinib resistance suggests that the use of multiple conformationally distinct kinase inhibitors will likely be better than any single agent. Using monotherapy, a single genetic event conferring resistance on an individual tumor cell can lead to clinical progression and indeed can be looked on as an inevitable consequence of a selection process under pressure of individual drugs, similar to the rationale for combination antibacterial or antiretroviral therapies. A better outcome will likely be achieved using combinations of targeted agents initially, in a manner analogous to that employed in treating HIV infection, to prevent rather than wait for treatment following the emergence of drug resistance (5, 6).

References

1. Wardelmann E, Merkelbach-Bruse S, Pauls K, et al. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 2006;12:1743–9.[Abstract/Free Full Text]
2. Debiec-Rychter M, Cools J, Dumez H, et al. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology 2005;128:270–9.[CrossRef][Medline]
3. Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 2005;11:4182–90.[Abstract/Free Full Text]
4. Shah NP, Nicoll JM, Nagar B, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002;2:117–25.[CrossRef][Medline]
5. Druker BJ. Overcoming resistance to imatinib by combining targeted agents. Mol Cancer Ther 2003;2:225–6.[Free Full Text]
6. Clay PG, Dong BJ, Sorensen SJ, Tseng A, Romanelli F, Antoniou T. Advances in human immunodeficiency virus therapeutics. Ann Pharmacother 2006;40:704–9.[Abstract/Free Full Text]

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