Secondary mutations of c-KIT contribute to acquired resistance to imatinib and decrease efficacy of sunitinib in Chinese patients with gastrointestinal stromal tumors

Abstract

The aim of this study was to investigate the associations between secondary mutations of c-KIT/PDGFRα and acquired imatinib resistance or efficacy of sunitinib in Chinese patients with gastrointestinal stromal tumors (GISTs). Mutations of c-KIT (exons 9, 11, 13, 14, 17, and 18) and PDGFRα (exons 12 and 18) in tumor samples of 50 patients were analyzed by direct sequencing. A total of 50 samples before imatinib and 52 samples after imatinib were collected. Among 52 samples after imatinib, 38 samples were imatinib resistant and 14 samples were imatinib sensitive. All patients before imatinib treatment had primary mutations of c-KIT exon 11 (n = 45) or exon 9 (n = 5), and no PDGFRα mutations were found in these patients. After imatinib treatment, 25 of 38 (65.8 %) resistant tumors had secondary mutations in c-KIT exon 13 (n = 10), exon 14 (n = 1), exon 17 (n = 12) and exon 18 (n = 2), while no secondary mutations of c-KIT were found in 14 sensitive tumors (P < 0.001), indicating the close association of c-KIT secondary mutations with imatinib-acquired resistance. In our study, 19 patients received sunitinib treatment after the failure of imatinib, and it seemed that the median progression-free survival (7 vs. 19 months, P = 0.244) in patients with secondary mutations (n = 13) was lower than that in patients without secondary mutations (n = 6). Secondary mutations of c-KIT were significantly associated with acquired resistance to imatinib in Chinese GIST patients, and whether secondary mutations of c-KIT could influence the efficacy of sunitinib needed to be further investigated.

Concordance of c‐kit Mutational Status in Matched Primary and Metastatic Cutaneous Canine Mast Cell Tumors at Baseline

“…The lymph node is the predominant site of metastases in the majority of dogs with metastatic MCT; therefore, the results of our study of 20 lymph node metastases provide a reference for clinical decision‐making as to TKI therapy. Nevertheless, as the molecular patterns might differ between metastatic sites,14, 38 and because c‐kit secondary mutations are likely to occur after TKIs administration,16, 39, 40 more results need to be obtained by testing additional metastatic sites, including spleen and liver, before and after targeted therapies. Also, the identification of new c‐kit ITDs underscores the need of further molecular investigations on their prognostic significance.…”

“…Moreover, the treatment with TKIs is associated with potential toxicity and high costs; additionally, resistance to certain TKIs is often caused by secondary mutations of c‐kit 7, 16; therefore, it is important to critically review all aspects of the mutational testing to enhance upfront patient selection.…”

“…15 In this study, we prospectively analyzed matched primary and metastatic MCT specimens for c-kit intraand intertumor heterogeneity (1) to give an insight into the mutational processes; and (2) to make a recommendation on the use of c-kit mutational analysis in the clinical setting. Moreover, the treatment with TKIs is associated with potential toxicity and high costs; additionally, resistance to certain TKIs is often caused by secondary mutations of c-kit 7,16 ; therefore, it is important to critically review all aspects of the mutational testing to enhance upfront patient selection.…”

Antitumor activity of sorafenib and imatinib in a patient with thymic carcinoma harboring c-KIT exon 13 missense mutation K642E

“…Some of these mutations appear to be associated with response to imatinib, while others are associated with resistance 15–17. Consistent with these findings, a few case reports on the effect of imatinib in patients with c-KIT-mutated thymic cancers have described favorable results: stable disease lasting 6 months was described in one patient with thymic carcinoma and a V560 deletion in exon 11 and a partial response lasting for 8 months in another with a missense mutation Y553N in exon 11 18,19…”

Second line of therapy for gastrointestinal stromal tumors: is there a choice?

“…С одной стороны, ведется поиск предикторов эффективности, с другой -изучаются преимущества профиля безопасности. Известно, что при развитии вторичной резистентности к иматинибу и сунитинибу в 30-40% случаев выявляется вторичная мутация с-KIT в 17 экзоне [73,74]. В исследование II фазы было включено 18 пациентов с ГИСО, у которых после прогрессирования на иматинибе или сунитинибе выявлялась мутация с-KIT в 17 экзоне.…”