FGFR-TKI resistance in cancer: current status and perspectives

AbstractFibroblast growth factor receptors (FGFRs) play key roles in promoting the proliferation, differentiation, and migration of cancer cell. Inactivation of FGFRs by tyrosine kinase inhibitors (TKI) has achieved great success in tumor-targeted therapy. However, resistance to FGFR-TKI has become a concern. Here, we review the mechanisms of FGFR-TKI resistance in cancer, including gatekeeper mutations, alternative signaling pathway activation, lysosome-mediated TKI sequestration, and gene fusion. In addition, we summarize strategies to overcome resistance, including developing covalent inhibitors, developing dual-target inhibitors, adopting combination therapy, and targeting lysosomes, which will facilitate the transition to precision medicine and individualized treatment.

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The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

10.20944/preprints202112.0282.v1 ◽

2021 ◽

Author(s):

Tadeusz Robak ◽

Magda Witkowska ◽

Piotr Smolewski

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Adverse Effects ◽

Kinase Inhibitors ◽

Clinical History ◽

Lymphocytic Leukemia ◽

Current Status ◽

Covalent Inhibitors ◽

History Of ◽

Reduced Toxicity ◽

Btk Inhibitors

The use of the Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKIs are classified into two categories: irreversible (covalent) inhibitors and reversible (non-covalent) inhibitors. Ibrutinib is the ﬁrst irreversible BTK inhibitor approved by the U.S. Food and Drug Administration in 2013 as a breakthrough therapy in CLL patients. Subsequently, several studies evaluated the efﬁcacy and safety of new agents with reduced toxicity when compared with ibrutinib. Two other irreversible, second-generation BTK inhibitors, acalabrutinib and zanubrutinib, were developed to reduce ibrutinib-mediated adverse effects. Additionally, new reversible BTK inhibitors are currently under development in an early phase studies to improve their activity and to diminish adverse effects. This review summarizes the pharmacology, clinical efficacy, safety, dosing, drug-drug interactions associated with the treatment of CLL with BTK inhibitors, and examines its further implications.

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CD117/c-kit Defines a Prostate CSC-Like Subpopulation Driving Progression and TKI Resistance

10.1101/256107 ◽

2018 ◽

Cited By ~ 1

Author(s):

Koran S. Harris ◽

Lihong Shi ◽

Brittni M. Foster ◽

Mary E. Mobley ◽

Phyllis L. Elliott ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Cancer Progression ◽

Kinase Inhibitors ◽

Marker Gene ◽

Dependent Manner ◽

Tumor Initiation ◽

Cancer Aggressiveness ◽

Tki Resistance ◽

And Migration

ABSTRACTCancer stem-like cells (CSCs) are associated with cancer progression, metastasis, and recurrence, and may also represent a subset of circulating tumor cells (CTCs). In our prior study, CTCs in advanced prostate cancer patients were found to express CD117/c-kit in a liquid biopsy. Whether CD117 expression played an active or passive role in the aggressiveness and migration of these CTCs remained an open question. In this study, we show that CD117 expression in prostate cancer patients is associated with decreased overall and progression-free survival and that activation and phosphorylation of CD117 increases in prostate cancer patients with higher Gleason grades. To determine how CD117 expression and activation by its ligand stem cell factor (SCF, kit ligand, steel factor) alter prostate cancer aggressiveness, we used LNCaP-C4-2 and PC3-mm human prostate cancer cells, which contain a CD117+ subpopulation. We demonstrate that CD117+ cells display increased proliferation and migration. In prostaspheres, CD117 expression enhances sphere formation. In both 2D and 3D cultures, stemness marker gene expression is higher in CD117+ cells. Using xenograft limiting dilution assays and serial tumor initiation assays, we show that CD117+ cells represent a CSC population. Combined, these data indicate that CD117 expression potentially promotes tumor initiation and metastasis. Further, in cell lines, CD117 activation by SCF promotes faster proliferation and invasiveness, while blocking CD117 activation with tyrosine kinase inhibitors (TKIs) decreased progression in a context-dependent manner. We demonstrate that CD117 expression and activation drives prostate cancer aggressiveness through the CSC phenotype and TKI resistance.

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CD117/c-kit defines a prostate CSC-like subpopulation driving progression and TKI resistance

Scientific Reports ◽

10.1038/s41598-021-81126-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Koran S. Harris ◽

Lihong Shi ◽

Brittni M. Foster ◽

Mary E. Mobley ◽

Phyllis L. Elliott ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Cancer Progression ◽

Kinase Inhibitors ◽

Marker Gene ◽

Dependent Manner ◽

Tumor Initiation ◽

Cancer Aggressiveness ◽

Tki Resistance ◽

And Migration

AbstractCancer stem-like cells (CSCs) are associated with cancer progression, metastasis, and recurrence, and may also represent a subset of circulating tumor cells (CTCs). In our prior study, CTCs in advanced prostate cancer patients were found to express CD117/c-kit in a liquid biopsy. Whether CD117 expression played an active or passive role in the aggressiveness and migration of these CTCs remained an open question. In this study, we show that CD117 expression in prostate cancer patients is associated with decreased overall and progression-free survival and that activation and phosphorylation of CD117 increases in prostate cancer patients with higher Gleason grades. To determine how CD117 expression and activation by its ligand stem cell factor (SCF, kit ligand, steel factor) alter prostate cancer aggressiveness, we used C4-2 and PC3-mm human prostate cancer cells, which contain a CD117+ subpopulation. We demonstrate that CD117+ cells display increased proliferation and migration. In prostaspheres, CD117 expression enhances sphere formation. In both 2D and 3D cultures, stemness marker gene expression is higher in CD117+ cells. Using xenograft limiting dilution assays and serial tumor initiation assays, we show that CD117+ cells represent a CSC population. Combined, these data indicate that CD117 expression potentially promotes tumor initiation and metastasis. Further, in cell lines, CD117 activation by SCF promotes faster proliferation and invasiveness, while blocking CD117 activation with tyrosine kinase inhibitors (TKIs) decreased progression in a context-dependent manner. We demonstrate that CD117 expression and activation drives prostate cancer aggressiveness through the CSC phenotype and TKI resistance.

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Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

Nature Communications ◽

10.1038/s41467-021-21396-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Hayato Mizuta ◽

Koutaroh Okada ◽

Mitsugu Araki ◽

Jun Adachi ◽

Ai Takemoto ◽

...

Keyword(s):

Gene Rearrangement ◽

Kinase Inhibitors ◽

Inhibitory Effect ◽

In Vivo Model ◽

Resistance Mutations ◽

Lung Cancer Patients ◽

Short Period ◽

Tki Resistance

AbstractALK gene rearrangement was observed in 3%–5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI–resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.

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Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia

Nature Communications ◽

10.1038/s41467-020-20259-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Hu Lei ◽

Han-Zhang Xu ◽

Hui-Zhuang Shan ◽

Meng Liu ◽

Ying Lu ◽

...

Keyword(s):

Tyrosine Kinase ◽

Progenitor Cells ◽

Chronic Myelogenous Leukemia ◽

Drug Targets ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Myelogenous Leukemia ◽

Tki Resistance

AbstractIdentifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin−Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML.

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Current Status of Fibroblast Growth Factor Receptor-Targeted Therapies in Breast Cancer

Cells ◽

10.3390/cells7070076 ◽

2018 ◽

Vol 7 (7) ◽

pp. 76 ◽

Cited By ~ 20

Author(s):

Navid Sobhani ◽

Anna Ianza ◽

Alberto D’Angelo ◽

Giandomenico Roviello ◽

Fabiola Giudici ◽

...

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor Receptor ◽

Growth Factor Receptor ◽

Metastatic Breast ◽

Tumor Formation ◽

Current Status ◽

Fibroblast Growth ◽

Fibroblast Growth Factor Receptors

Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, metastatic breast cancer has a poor prognosis. In an era of personalized medicine, there is an urgent need for better knowledge of the biology leading to the disease, which can lead to the design of increasingly accurate drugs against patients’ specific molecular aberrations. Among one of the actionable targets is the fibroblast growth factor receptor (FGFR) pathway, triggered by specific ligands. The Fibroblast Growth Factor Receptors/Fibroblast Growth Factors (FGFRs/FGFs) axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of FGFR mutations, which lead to tumor formation and summarizes the state-of-the-art therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC.

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Antioxidant Therapy in Pancreatitis

Antioxidants ◽

10.3390/antiox10050657 ◽

2021 ◽

Vol 10 (5) ◽

pp. 657

Author(s):

Lourdes Swentek ◽

Dean Chung ◽

Hirohito Ichii

Keyword(s):

Oxidative Stress ◽

Chronic Pancreatitis ◽

Total Pancreatectomy ◽

Current Status ◽

Related Factor ◽

Endocrine Dysfunction ◽

Deep Dive ◽

Pathway Activation ◽

Advanced Therapies ◽

And Oxidative Stress

Pancreatitis is pathologic inflammation of the pancreas characterized by acinar cell destruction and oxidative stress. Repeated pancreatic insults can result in the development of chronic pancreatitis, characterized by irreversible fibrosis of the pancreas and many secondary sequelae, ultimately leading to the loss of this important organ. We review acute pancreatitis, chronic pancreatitis, and pancreatitis-related complications. We take a close look at the pathophysiology with a focus on oxidative stress and how it contributes to the complications of the disease. We also take a deep dive into the evolution and current status of advanced therapies for management including dietary modification, antioxidant supplementation, and nuclear factor erythroid-2-related factor 2-Kelch-like ECH-associated protein 1(Nrf2-keap1) pathway activation. In addition, we discuss the surgeries aimed at managing pain and preventing further endocrine dysfunction, such as total pancreatectomy with islet auto-transplantation.

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Worldwide Overview of the Current Status of Lung Cancer Diagnosis and Treatment

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2012-0295-sa ◽

2012 ◽

Vol 136 (12) ◽

pp. 1478-1481 ◽

Cited By ~ 35

Author(s):

Paul A. Bunn

Keyword(s):

Lung Cancer ◽

Cancer Mortality ◽

Kinase Inhibitors ◽

False Positive Rate ◽

Lung Cancer Mortality ◽

Current Status ◽

Advanced Lung Cancer ◽

Lung Cancer Diagnosis ◽

Positive Rate ◽

Inhaled Prostacyclin

Lung cancer is the leading worldwide cause of cancer deaths. Smoking is the dominant cause of lung cancer and smoking cessation is the established method to reduce lung cancer mortality. While lung cancer risk is reduced in former smokers, they have a lifelong increase in risk, compared to never-smokers. Novel chemoprevention strategies, such as oral or inhaled prostacyclin analogs, hold promise for these subjects. Low-dose spiral computed tomography screening reduced lung cancer mortality by 20% in high-risk heavy smokers older than 50 years. However, the high false-positive rate (96%) means that screened patients required controlled follow-up in experienced centers. An increasing percentage of patients with advanced lung cancer have molecular drivers in genes for which oral tyrosine kinase inhibitors have been developed.

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Emerging Paradigms in the Development of Resistance to Tyrosine Kinase Inhibitors in Lung Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2012.45.2029 ◽

2013 ◽

Vol 31 (31) ◽

pp. 3987-3996 ◽

Cited By ~ 198

Author(s):

Justin F. Gainor ◽

Alice T. Shaw

Keyword(s):

Lung Cancer ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Genetic Alterations ◽

Anaplastic Lymphoma ◽

Development Of Resistance ◽

Tki Resistance ◽

Alk Positive ◽

Egfr Mutant

The success of tyrosine kinase inhibitors (TKIs) in select patients with non–small-cell lung cancer (NSCLC) has transformed management of the disease, placing new emphasis on understanding the molecular characteristics of tumor specimens. It is now recognized that genetic alterations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) define two unique subtypes of NSCLC that are highly responsive to genotype-directed TKIs. Despite this initial sensitivity, however, the long-term effectiveness of such therapies is universally limited by the development of resistance. Identifying the mechanisms underlying this resistance is an area of intense, ongoing investigation. In this review, we provide an overview of recent experience in the field, focusing on results from preclinical resistance models and studies of patient-derived, TKI-resistant tumor specimens. Although diverse TKI resistance mechanisms have been identified within EGFR-mutant and ALK-positive patients, we highlight common principles of resistance shared between these groups. These include the development of secondary mutations in the kinase target, gene amplification of the primary oncogene, and upregulation of bypass signaling tracts. In EGFR-mutant and ALK-positive patients alike, acquired resistance may also be a dynamic and multifactorial process that may necessitate the use of treatment combinations. We believe that insights into the mechanisms of TKI resistance in patients with EGFR mutations or ALK rearrangements may inform the development of novel treatment strategies in NSCLC, which may also be generalizable to other kinase-driven malignancies.

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