PI3K/AKT/mTOR pathway is activated after imatinib secondary resistance in gastrointestinal stromal tumors (GISTs)

Abstract

Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) pathway activation may be related to imatinib resistance; however, no study has focused on whether signal conduction of this pathway will change after imatinib resistance. A total of 111 GIST samples from 91 patients were used in this study, including 20 pairs of samples before and after imatinib treatment. Immunohistochemistry was performed on tissue for p-KIT (phospho-KIT), PTEN (phosphatase and tensin homolog deleted on chromosome ten), PI3K, phospho-AKT (p-AKT), phospho-4EBP1 (p-4EBP1) and phospho-S6 (p-S6RP). The activation of AKT/mTOR was significantly higher in imatinib secondary resistant GIST (53.1 %) than in imatinib-sensitive (27.1 %) and primary resistant GIST (33.3 %) (P = 0.049). In the analysis of 20 pairs of samples, comparing pre-imatinib GIST with on-treatment ones, the PI3K status was changed from inactivated to activated in four cases each in eight patients with effective imatinib and 12 patients whose secondary resistance happened, respectively. AKT/mTOR status was inactivated in pre-imatinib and on-treatment samples in eight patients with effective imatinib; however, the status of six patients was changed from inactivated to activated in 12 patients at the time of tumor progression. The negative expression of p-KIT was accompanied with PI3K pathway and/or AKT/mTOR pathway activity in some GISTs with secondary resistance. PI3K/AKT/mTOR pathway can be partly activated after imatinib secondary resistance in GIST. In this pathway, activation of AKT/mTOR is a more crucial factor, and PI3K activation may be the early part of secondary resistance.

Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors

“…Also, in the metastatic/high‐risk tumor samples, no correlations between them were found ( P = 4.0 × 10 −1 , P = 1.8 × 10 −1 , respectively). The PI3K pathway has been reported to be activated as a result of imatinib secondary resistance . In the present study, we observed PI3K pathway alteration even in tumor samples derived from patients not treated with neoadjuvant imatinib.…”

“…In addition to LOH of PTEN , we dominantly identified genetic alterations of PI3K pathway genes in malignant GIST samples with metastatic or high‐risk group, including oncogenic activation by PIK3CA mutations and copy number gain with expression enhancement in AKT1 and RICTOR , and tumor‐suppressive inactivation by LOH or expression reduction of TSC1/2 , and NPRL3 (Figure ). The PI3K pathway has been reported to be activated as a result of imatinib secondary resistance, including GIST . In the present study, we observed PI3K pathway alteration even in tumor samples derived from patients who were not treated with neoadjuvant imatinib, suggesting that PI3K activation was irrelevant to imatinib treatment in metastatic and high‐risk GIST.…”

“…Genes with the remainder of the four deleterious mutations, along with 27 genes harboring the missense and in‐frame deletion mutations, can disrupt tumor‐suppressive function of protein by haploinsufficiency or dominant‐negative effect. However, according to the ACMG standards and guidelines described previously, the nonsense USP44 mutation was predicted to maintain its function as a result of its location on the penultimate exon. Thus, considering the types of mutations and locations, four deleterious mutations in RBM10 , CHD2 , MGA , and MAML3 were designated as ‘very likely’ for TSG inactivation.…”

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

“…Although these inhibitors have revolutionized the treatment of GIST and other malignancies, management of intrinsic and acquired resistance mechanisms remain a clinical challenge. Activation of the PI3K/AKT pathway, downstream of activated RTKs, has been shown to both predict and promote resistance to RTK inhibitors in GIST and in other malignancies (7,9,10,39-41). Clinical trials are currently underway to investigate the use of PI3K/AKT inhibitors in combination with RTK inhibitors in CLL, melanoma, and NSCLC.…”

Evolutionary scalpels for dissecting tumor ecosystems

“…It is unclear whether the treatment periods of two weeks to four months in the above experiments would have been sufficient time for the appearance of resistance to dual therapy. Furthermore, while inhibition of KIT blocks activation of the downstream PI3K/AKT signaling pathway in imatinib-sensitive tumors, overexpression 75 or KIT-independent activation 76 of components in this pathway can contribute to imatinib resistance. Understanding interactions between inhibitors of KIT and of the PI3K/AKT pathway, as well as the (possibly overlapping!)…”