Targeted therapy for drug-tolerant persister cells after imatinib treatment for gastrointestinal stromal tumours

2021 ◽  
Author(s):  
Tomo Ishida ◽  
Tsuyoshi Takahashi ◽  
Yukinori Kurokawa ◽  
Toshirou Nishida ◽  
Seiichi Hirota ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Imatinib Treatment ◽  
Gastrointestinal Stromal Tumours ◽  
Persister Cells

scholarly journals Adjuvant imatinib treatment improves recurrence-free survival in patients with high-risk gastrointestinal stromal tumours (GIST)

2007 ◽  
Vol 96 (11) ◽  
pp. 1656-1658 ◽  
Author(s):  
B Nilsson ◽  
K Sjölund ◽  
L-G Kindblom ◽  
J M Meis-Kindblom ◽  
P Bümming ◽  
...  
Keyword(s):  
High Risk ◽  
Imatinib Treatment ◽  
Recurrence Free Survival ◽  
Adjuvant Imatinib ◽  
Gastrointestinal Stromal Tumours ◽  
Free Survival

scholarly journals Case Report: Long-Term Response to Radiotherapy Combined With Targeted Therapy in Histiocytic Sarcoma Harboring Mutations in MAPK and PI3K/AKT Pathways

2021 ◽  
Vol 11 ◽  
Author(s):  
Zijian Liu ◽  
Yin Xiao ◽  
Xinxiu Liu ◽  
Qiuhui Li ◽  
Tao Liu ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Histiocytic Sarcoma ◽  
Mitogen Activated Protein Kinase ◽  
Cell Counting ◽  
Pathway Enrichment Analysis ◽  
Imatinib Treatment ◽  
Inhibitory Effects ◽  
Poor Overall Survival ◽  
Hematopoietic Malignancy

BackgroundHistiocytic sarcoma (HS) is a rare hematopoietic malignancy with an aggressive clinical presentation associated with a poor overall survival. To date, surgical resection, radiation therapy, and chemotherapy were often utilized for HS, but curative effects are rather disappointing.Case PresentationA 19-year-old female was referred to our hospital with a pathologic diagnosis of HS in December 2017. The patient had a severe airway obstruction resulting from a large mass (6.0 cm × 4.4 cm) arising from the left parapharyngeal space. She did not respond to cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOEP) chemotherapy, then she was switched to radiotherapy and crizotinib according to next-generation sequencing (NGS) results (mutations in MET and MAP2K1). The patient got a partial response after radiotherapy and crizotinib, then she switched to imatinib combined with thalidomide treatment. The patient got a long-term complete response from the treatment and is alive 44 months after initial diagnosis without disease progression. Further KEGG pathway enrichment analysis of NGS results from patient’s tissue revealed that phosphatidylinositol 3′ kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) pathways were activated in this HS patient. We further performed experiments in vitro in a canine histiocytic sarcoma cell line DH82, in order to explore the possible mechanism of imatinib plus thalidomide in HS. Results of cell counting kit-8 (CCK8) assays showed that the proliferation activity of DH82 was significantly inhibited by imatinib but not thalidomide. Combined thalidomide and imatinib treatment did not improve the inhibitory effects of imatinib to DH82. Results of Western blot confirmed the inhibitory effects of imatinib on DH82 by targeting activation of MAPK and PI3K/AKT pathways.ConclusionRadiotherapy combined with targeted therapy guided by NGS may be promising, and further perspective clinical trial is warranted for the localized HS.

scholarly journals Targeted therapy of gastrointestinal stromal tumours

2016 ◽  
Vol 8 (5) ◽  
pp. 345 ◽  
Author(s):  
Ashish Jakhetiya ◽  
Pankaj Kumar Garg ◽  
Gaurav Prakash ◽  
Jyoti Sharma ◽  
Rambha Pandey ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Gastrointestinal Stromal Tumours

scholarly journals A focal adhesion kinase-YAP signaling axis drives drug tolerant persister cells and residual disease in lung cancer

2021 ◽  
Author(s):  
Franziska Haderk ◽  
Celia Fernandez-Mendez ◽  
Lauren Cech ◽  
Johnny Yu ◽  
Ismail M. Meraz ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Targeted Therapies ◽  
Residual Disease ◽  
Persister Cells ◽  
Cancer Models ◽  
Signaling Axis ◽  
Tumor Types

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant tumor cells which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.

Caveolin-1 expression predicts favourable outcome and correlates with PDGFRA mutations in gastrointestinal stromal tumours (GISTs)

2021 ◽  
pp. jclinpath-2021-207595
Author(s):  
Luca Bertero ◽  
Alessandro Gambella ◽  
Antonella Barreca ◽  
Simona Osella-Abate ◽  
Luigi Chiusa ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Significance ◽  
Favourable Outcome ◽  
Imatinib Treatment ◽  
Gastrointestinal Stromal Tumours ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Multifunctional Protein ◽  
Caveolin 1 ◽  
Molecular Features

AimsNovel prognostic markers are warranted for gastrointestinal stromal tumours. Caveolin-1 is a multifunctional protein that proved to be associated with outcome in multiple tumour types. Aim of this study was to investigate Caveolin-1 expression and prognostic efficacy in a series of gastrointestinal stromal tumours.MethodsCaveolin-1 expression was assessed by immunohistochemistry in a retrospective series of 66 gastrointestinal stromal tumours representative of the different molecular subtypes. Correlations with clinical, histopathological and molecular features were investigated. Statistical analyses were performed as appropriate.ResultsThirty-five cases out of 66 (53.0%) expressed Caveolin-1. Presence of Caveolin-1 expression correlated with favourable histopathologic and clinical traits, including a lower mitotic count (p=0.003) and lower relapse rate (p=0.005). Caveolin-1 expression also resulted associated with the presence of PDGFRA mutations (p=0.010). Outcome analyses showed a favourable prognostic significance of Caveolin-1 expression in terms of relapse-free survival (HR=0.14; 95% CI=0.03 to 0.63) and overall survival (HR=0.29; 95% CI=0.11 to 0.74), even after adjusting for the mutational subgroup (relapse-free survival: HR=0.14, 95% CI=0.04 to 0.44; overall survival: HR=0.29, 95% CI=0.11 to 0.51) and imatinib treatment (relapse-free survival: HR=0.14, 95% CI=0.02 to 0.81; overall survival: HR=0.29, 95% CI=0.17 to 0.48).ConclusionCaveolin-1 represents a novel prognostic marker in gastrointestinal stromal tumours. Further studies are warranted to validate these results and to explore the mechanisms linking Caveolin-1 expression with the PDGFRA oncogenic pathway.

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