BRAF Mutant Gastrointestinal Stromal Tumor: First report of regression with BRAF inhibitor dabrafenib (GSK2118436) and whole exomic sequencing for analysis of acquired resistance

Abstract

Activating oncogenic mutations of BRAF have been described in patients with gastrointestinal stromal tumor (GIST), but treatment of GIST with BRAF inhibitors and mechanisms of mediating the emergence of resistance in GIST have not been reported. Dabrafenib is a potent ATP-competitive inhibitor of BRAF kinase and is highly selective for mutant BRAF in kinase panel screening, cell lines, and xenografts. We report prolonged antitumor activity in the first patient with V600E BRAF-mutated GIST who was treated with a BRAF inhibitor. Whole exome sequencing performed in tumor tissue obtained at the time of progressive disease demonstrated a somatic gain-of-function PIK3CA mutation (H1047R) as well as a CDKN2A aberration, which may have contributed to eventual resistance to treatment.

Frequency and clinicopathologic profile of PIK3CA mutant GISTs: molecular genetic study of 529 cases

“…This codon was mutated in all three previously reported PIK3CA mutant GISTs. [7][8][9] Thus, similarly to other cancer, p.H1047 appears to be the most common mutational hotspot in GISTs. One tumor revealed two co-existing PIK3CA exon 20 mutations.…”

“…7 One PIK3CA mutation was reported in KIT/PDGFRA-wild type, BRAF V600E mutant GIST metastasis during BRAF-inhibitor treatment, at the time of disease progression. 8 Primary GISTs driven by BRAF mutations are exceptionally rare. 7,17 In the current study, PIK3CA was evaluated in one BRAF mutant GIST and revealed wild-type sequences.…”

“…5,6 Recently, PIK3CA mutations have been reported in two primary gastric GISTs: one concurrent with a KIT mutation and another with the HRAS mutation, and in treatment-resistant metastasis of a BRAF-mutant GIST. [7][8][9] Thus, activation of the PI3K/AKT/mTOR signaling pathway may have a role in both pathogenesis and the progression of GISTs. The presence of the PIK3CA mutation could indicate an alternative treatment inhibiting the PI3K/AKT/ mTOR signaling pathway for patients with advanced and metastatic tumors, as opposed to KIT inhibitor therapy.…”

Molecular features and genetic markers of gastrointestinal stromal tumors

“…Все случаи ГИСО c мутацией BRAF представляли собой высокозлокачественные стро-мальные опухоли тонкой кишки у женщин в воз-расте 49-55 лет. Впервые ингибирование BRAF-положительной ГИСО получено при использовании ингибитора BRAF дабрафениба у пациента с мутацией V600E [78]. Однако через 6 мес появилась устойчи-вость к препарату, которую связывают с мутацией PIK3CA (H1047R) и нарушениями CDKN2A, что было установлено при полноэкзомном секвенировании [78].…”

Therapeutic strategies for wild-type gastrointestinal stromal tumor: is it different from KIT or PDGFRA-mutated GISTs?

“…Recent small cohort studies and sub-analysis of clinical trials indicate that inhibitors for vascular endothelial growth factor receptor, such as sunitinib, regorafenib, and pazopanib, may have significant activities on SDH-deficient GISTs (16)(17)(18). GISTs with typical BRAF mutations (V600E) were indicated to be sensitive to BRAF and/or MEK inhibitors (15). Some translational investigations indicate that the proliferation of NF1-GISTs may be potentially controlled by MEK1/2 inhibitors (14).…”