KIT and PDGFRA mutations in gastrointestinal stromal tumors) and (ii) sarcomas displaying multiple, complex karyotypic abnormalities with no specific pattern, including leiomyo-sarcoma, and pleomorphic liposarcoma.
Exposure of sarcoma and PDX ovarian carcinoma cells to [pazopanib + entinostat] caused a prolonged activation of ERBB1 and transient/prolonged activations of ERBB2, c-KIT, and c-MET, in a cell-specific fashion.
The identification of activating KIT mutations in the majority of GISTs was a defining moment that led to the first effective targeted therapy for sarcoma, and the subsequent use of imatinib mesylate has revolutionized the treatment of GISTs.
During this period, this distinct disease entity was identified under various acronyms (GIST remaining the most commonly used), the molecular basis of disease transformation (i.e. activating c-KIT mutations) was identified in sporadic and familial cases, and finally GIST was identified as the sarcoma subtype most resistant to chemotherapy in both retrospective and prospective studies.
Furthermore, the determination of the relationship of specific KIT mutations and sensitivity and resistance to kinase-directed agents and the assessment of inhibitor levels and the quality of response to those agents have implications beyond the treatment of sarcomas.
The most common mutation was in the ret proto-oncogene, which occurred in 47 cases followed by mutations in genes encoding Harvey rat sarcoma viral oncogene homolog (N = 14), serine/threonine kinase 11 (N = 11), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (N = 6), mutL homolog 1 (N = 4), Kiesten rat sarcoma viral oncogene homolog (N = 3) and MET proto-oncogene (N = 3).
<b>Purpose:</b> A phase Ib study of dasatinib plus ipilimumab in patients with gastrointestinal stromal tumor (GIST) and other sarcomas was performed on the basis of preclinical data demonstrating that combined KIT and CTLA-4 blockade is synergistic.<b>Experimental Design:</b> A standard 3 + 3 design was used to evaluate the safety, efficacy, and immune correlates of treatment.