Preclinical model-based evaluation of Imatinib resistance induced by KIT mutations and its overcoming strategies in gastrointestinal stromal tumor (GIST).

ABSTRACT:

Background

The potential correlation between KIT secondary mutations and Imatinib-resistance in gastrointestinal stromal tumor (GIST) has been hinted, yet their specific linkage and underlying mechanisms remained unelucidated, also the development of substitute strategies dealing with this resistance was urgently needed.

Methods

In this study, we explored the distribution of the most prevalent forms of KIT mutation in Chinese GIST patients, after that, we established cell lines that was overexpressed with mutant KIT, and by performing RNA sequencing, immunoblotting and cell viability, we analyzed their functional and mechanistic relevance with Imatinib-resistance in GIST cell lines. Additionally, we evaluated the tumor inhibition efficacy of four regimens in Imatinib-resistant GIST cell lines and patient-derived xenograft (PDX) models.

Results

We found that KIT exon 13-V654A and exon 17-N822K were the most common secondary mutations in GIST with primary exon 11 mutations. These two secondary mutations induced Imatinib resistance by activating PI3K-Akt signaling pathway, while PI3K-Akt inhibition rescued the resistance. By assessing the feasibility of other four tyrosine kinase inhibitor (TKIs, Sunitinib/Regorafenib/Avapritinib/Ripretinib) against Imatinib-resistant GIST, we found that Sunitinib was more suitable for KIT exon 13 secondary mutations, the rest were more effective for KIT exon 17 secondary mutations, while all four TKIs displayed efficacy for KIT exon 9 mutations, emphasizing their clinical applications against Imatinib resistance.

Conclusions

We demonstrated the mechanism by which KIT secondary mutations on exon 13/17 cause Imatinib resistance to GIST, and validated that several novel TKIs were valuable therapeutic options against Imatinib-resistance for both secondary- and primary-KIT mutations.

SUBMITTER: Zhao Q 

PROVIDER: S-EPMC8748123 | biostudies-literature |

REPOSITORIES: biostudies-literature