Systemic Therapy
Imatinib - Resistance
Multiple potential molecular mechanisms of resistance to Glivec in GIST have been proposed, both KIT dependent and KIT independent.1-3
KIT-dependent mechanisms include secondary activating mutations of KIT, KIT overexpression, or gene amplification of KIT. KIT-independent mechanisms include loss of KIT expression, increased Glivec® metabolism (eg, increased p450 and/or α-1 acid glycoprotein activity), activating mutations in alternative receptor tyrosine kinases that converge on the same downstream signaling molecules as KIT, direct activation of these downstream signal transduction pathways, and the development of multidrug resistance (eg, overexpression of P-glycoprotein). Many of the proposed mechanisms of Glivec resistance have been documented in molecular analyses of progressing GISTs in patients treated with Glivec.2-8
Although the original study B2222 mutational analysis of 127 patients with metastatic GIST documented that no patient exhibited more than one KIT-activating mutation,9 subsequent studies have documented the occurrence of more than one KIT-activating mutation in GIST patients progressing on Glivec.
Desai et al provided the first evidence supporting a hypothesis for clonal evolution of GIST cells to Glivec resistance. The investigators reported that 48 of 89 advanced GIST patients treated with Glivec progressed after a meian of 43 months, during which they had achieved at least a partial or minor level of response to Glivec.4 omputed tomography imaging detected recurrence as a new enhancing nodular focus contained within an already existing tumor mass. Biopsies were performed on tumors before therapy and during progression in 10 patients. Genetic analysis at baseline identified KIT mutations in exon 11 (n = 8) and exon 13 (n = 2); 8 of the progressing tumors associated with these original GISTs had acquired additional KIT-activating mutations in exon 17 or exon 13.
Further support for this hypothesis was obtained from 2 subsequent case reports describing patients with advanced GIST with initial responses to Glivec followed by the development of progressing peritoneal masses.5,6 In the first case, analysis of the original masses and the progressing tumor indicated that all lesions exhibited a mutation in exon 11; however, the progressing lesion also harbored a novel point mutation in KIT exon 14, resulting in a T670I substitution in the ATP-binding region of KIT, which is critical for Glivec binding. The substitution is therefore likely to reduce Glivec binding with KIT, making the secondarily mutated kinase insensitive to Glivec. In the second case, the primary tumor was found to contain mutations in exon 11, and the relapsed metastatic tumor had a Y823D substitution in the second KIT kinase domain as well as the original mutations in exon 11.
Chen et al followed 12 GIST patients with initial responses to Glivec®; 7 and 5 of these patients harbored mutations in exon 11 and exon 9, respectively. Five patients developed progressive disease within 30 months. Genetic analysis revealed that all progressive tumors from these patients harbored both the original activating KIT mutation and a KIT mutation encoding a V654A substitution in the first tyrosine kinase domain of KIT. The correlation of clinical resistance to Glivec with the presence of this secondary mutation suggests that this KIT mutant is responsible for Glivec resistance.
Another study screened for mutations in regions of KIT or PDGFRA encoding kinase domains among 26 Glivec-resistant GISTs.3 Among these progressing tumors, 12 exhibited secondary point mutations in KIT, including V654A, T670I, D716N, D820E, N822K, and D816G substitutions. The last 3 of these mutations occurred in the activation loop of the second KIT catalytic domain and thus are likely to both activate the kinase and confer Glivec resistance. One resistant GIST harbored a D842V substitution in PDGFRα, the most common activating PDGFRA mutation in GIST.
Antonescu et al investigated 31 GIST patients in an effort to identify the mechanism of acquired resistance to Glivec.8 Three patients had primary resistance, and 15 had acquired resistance after an initial response to treatment; 13 patients demonstrated no resistance to Glivec. In 46% of patients with acquired resistance, secondary mutations of exon 11 were revealed; no secondary mutations in KIT or PDGFRA appeared in either nonresistant or primary-resistance patients.
Together, these research findings indicate that secondary KIT-activating mutations are the most common mechanism of Glivec resistance in GIST but that PDGFRA mutations can also confer resistance.
Two patients in the Debiec-Rychter study discussed above had Glivec resistance associated with KIT or KIT and PDGFRA gene amplification in addition to secondary mutations.3 Two other resistant patients in this study demonstrated complete loss of KIT expression, suggesting a mechanism of Glivec resistance independent of KIT. Yamaguchi et al described a patient with secondary resistance to Glivec and no mutation in exon 9, 11, 13, or 17, indicating that secondary resistance attributable to unknown molecular mechanisms is also observed. Secondary KIT mutations, however, are currently the most common explanation for Glivec resistance.7
References:
1. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22:3813-3825.
2. Chen LL, Sabripour M, Andtbacka RH, et al. Imatinib resistance in gastrointestinal stromal tumors. Curr Oncol Rep. 2005;7:293-299.
3. 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;128:270-279.
4. Desai J, Shankar S, Heinrich MC, et al. Clonal evolution of resistance to imatinib (IM) in patients (pts) with gastrointestinal stromal tumor (GIST): molecular and radiologic evaluation of new lesions [abstract]. Proc Am Soc Clin Oncol. 2004;23:197. Abstract 3010.
5. Tamborini E, Bonadiman L, Greco A, et al. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology. 2004;127:294-299.
6. Wakai T, Kanda T, Hirota S, et al. Late resistance to imatinib therapy in a metastatic gastrointestinal stromal tumour is associated with a second KIT mutation. Br J Cancer. 2004;90:2059-2061.
7. Yamaguchi M, Matsumoto T, Tate G, Higuchi T. Secondary resistance to imatinib mesylate in a patient with unresectable duodenal GIST without mutations in exons 9, 11, 13, or 17 of the c-kit protooncogene. J Gastroenterol. 2004;39:904-905.
8. 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;11:4182-4190.
9. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342-4349.