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Cancers
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Tyrosine Kinase Inhibitors (TKIs) in Cancer Targeted Therapy
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Tyrosine Kinase Inhibitors (TKIs) in Cancer Targeted Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 10125

Special Issue Editor

Dr. Olga Martinho

E-Mail Website
Guest Editor
PhD in Health Sciences, Auxiliary Researcher at Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
Interests: molecular-targeted therapies in cancer; oncogenic signaling pathways; prognostic biomarkers; cancer metabolism; molecular mechanisms of therapy resistance in oncology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

An ideal anticancer strategy would be one that selectively restricts the proliferation and survival of tumor cells while sparing normal cells. Molecular targeted therapies, which are tailored to interfere specifically with the key molecular aberrations that drive the malignant phenotype, are designed to meet this criterion, holding great promise for expanding the therapeutic window in cancer. The definition of signaling pathways to understand tumor biology, combined with the rapid development of technologies that allow for high-throughput molecular analysis of tumors, has led to a new era of precision medicine in oncology, with the development of drugs targeted against oncogenic tyrosine kinases. A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases, which are enzymes responsible for the activation of many proteins by signal transduction cascades.

Although the concept of oncogene addiction has led to some initially impressive clinical results, it is also apparent that tumors can often escape their oncogene addicted state, causing relapse of the tumor even after pronounced initial responses. Thus, the main challenge in precision oncology includes both the identification of tyrosine kinases that enable selection of patient populations that are most likely to benefit from the treatment and anticipation of the driven resistance molecular mechanisms.

This Special Issue will highlight the importance of tyrosine kinases targeted therapies in oncological patient’s management, covering new basic and preclinical discoveries on the field of predictive biomarkers or resistance drivers to TKI in cancer patients.

Dr. Olga Martinho
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • molecular targeted therapies
  • TKI inhibitors
  • oncogene signaling pathways
  • precision oncology
  • predictive biomarkers
  • therapy resistance

Published Papers (5 papers)

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Research

14 pages, 1827 KiB  
Article
Clinical Outcomes of Cabozantinib in Patients Previously Treated with Atezolizumab/Bevacizumab for Advanced Hepatocellular Carcinoma—Importance of Good Liver Function and Good Performance Status
by Teiji Kuzuya, Naoto Kawabe, Mizuki Ariga, Eizaburo Ohno, Kohei Funasaka, Mitsuo Nagasaka, Yoshihito Nakagawa, Ryoji Miyahara, Tomoyuki Shibata, Takeshi Takahara, Yutaro Kato and Yoshiki Hirooka
Cancers 2023, 15(11), 2952; https://doi.org/10.3390/cancers15112952 - 28 May 2023
Cited by 3 | Viewed by 1787
Abstract
(1) Background: This study aimed to investigate clinical outcomes for cabozantinib in clinical practice in patients with advanced hepatocellular carcinoma (HCC) previously treated with atezolizumab plus bevacizumab (Atz/Bev), with a focus on whether patients met criteria of Child–Pugh Class A and Eastern Cooperative [...] Read more.
(1) Background: This study aimed to investigate clinical outcomes for cabozantinib in clinical practice in patients with advanced hepatocellular carcinoma (HCC) previously treated with atezolizumab plus bevacizumab (Atz/Bev), with a focus on whether patients met criteria of Child–Pugh Class A and Eastern Cooperative Oncology Group performance status (ECOG-PS) score 0/1 at baseline. (2) Methods: Eleven patients (57.9%) met the criteria of both Child–Pugh class A and ECOG-PS score 0/1 (CP-A+PS-0/1 group) and eight patients (42.1%) did not (Non-CP-A+PS-0/1 group); efficacy and safety were retrospectively evaluated. (3) Results: Disease control rate was significantly higher in the CP-A+PS-0/1 group (81.1%) than in the non-CP-A+PS-0/1 group (12.5%). Median progression-free survival, overall survival and duration of cabozantinib treatment were significantly longer in the CP-A+PS-0/1 group (3.9 months, 13.4 months, and 8.3 months, respectively) than in the Non-CP-A+PS-0/1 group (1.2 months, 1.7 months, and 0.8 months, respectively). Median daily dose of cabozantinib was significantly higher in the CP-A+PS-0/1 group (22.9 mg/day) than in the non-CP-A+PS-0/1 group (16.9 mg/day). (4) Conclusions: Cabozantinib in patients previously treated with Atz/Bev has potential therapeutic efficacy and safety if patients have good liver function (Child–Pugh A) and are in good general condition (ECOG-PS 0/1). Full article
(This article belongs to the Special Issue Tyrosine Kinase Inhibitors (TKIs) in Cancer Targeted Therapy)
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20 pages, 12931 KiB  
Article
Vascular Niche Facilitates Acquired Drug Resistance to c-Met Inhibitor in Originally Sensitive Osteosarcoma Cells
by Weifeng Tang, Yu Zhang, Haixia Zhang and Yan Zhang
Cancers 2022, 14(24), 6201; https://doi.org/10.3390/cancers14246201 - 15 Dec 2022
Cited by 2 | Viewed by 1487
Abstract
Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents characterized by drug resistance and poor prognosis. As one of the key oncogenes, c-Met is recognized as a promising therapeutic target for OS. In this report, we show that c-Met [...] Read more.
Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents characterized by drug resistance and poor prognosis. As one of the key oncogenes, c-Met is recognized as a promising therapeutic target for OS. In this report, we show that c-Met inhibitor PF02341066 specifically killed OS cells with highly phosphorylated c-Met in vitro. However, the inhibitory effect of PF02341066 was abrogated in vivo due to interference from the vascular niche. OS cells adjacent to microvessels or forming vascular mimicry suppressed c-Met expression and phosphorylation. Moreover, VEGFR2 was activated in OS cells and associated with acquired drug resistance. Dual targeting of c-Met and VEGFR2 could effectively shrink the tumor size in a xenograft model. c-Met-targeted therapy combined with VEGFR2 inhibition might be beneficial to achieve an ideal therapeutic effect in OS patients. Together, our results confirm the pivotal role of tumor heterogeneity and the microenvironment in drug response and reveal the molecular mechanism underlying acquired drug resistance to c-Met-targeted therapy. Full article
(This article belongs to the Special Issue Tyrosine Kinase Inhibitors (TKIs) in Cancer Targeted Therapy)
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9 pages, 1266 KiB  
Article
High-Dose Intermittent Treatment with the Multikinase Inhibitor Sunitinib Leads to High Intra-Tumor Drug Exposure in Patients with Advanced Solid Tumors
by Sophie L. Gerritse, Mariette Labots, Rob ter Heine, Henk Dekker, Dennis Poel, Daniele V. F. Tauriello, Iris D. Nagtegaal, Erik Van Den Hombergh, Nielka Van Erp and Henk M. W. Verheul
Cancers 2022, 14(24), 6061; https://doi.org/10.3390/cancers14246061 - 9 Dec 2022
Cited by 3 | Viewed by 1301
Abstract
Patients with advanced cancer refractory to standard treatment were treated with sunitinib at a dose of 300 mg once every week (Q1W) or 700 mg once every two weeks (Q2W). Tumor, skin and plasma concentrations were measured and immunohistochemical staining for tumor cell [...] Read more.
Patients with advanced cancer refractory to standard treatment were treated with sunitinib at a dose of 300 mg once every week (Q1W) or 700 mg once every two weeks (Q2W). Tumor, skin and plasma concentrations were measured and immunohistochemical staining for tumor cell proliferation (TCP), microvessel density (MVD) and T-cell infiltration was performed on tumor biopsies before and after 17 days of treatment. Oral administration of 300 mg sunitinib Q1W or 700 mg Q2W resulted in 19-fold (range 5–35×) and 37-fold higher (range 10–88×) tumor drug concentrations compared to parallel maximum plasma drug concentrations, respectively. Patients with higher tumor sunitinib concentrations had favorable progression-free and overall survival than those with lower concentrations (p = 0.046 and 0.024, respectively). In addition, immunohistochemistry of tumor biopsies revealed an induction of T-cell infiltration upon treatment. These findings provide pharmacological and biological insights in the clinical benefit from high-dose intermittent sunitinib treatment. It emphasizes the potential benefit from reaching higher tumor drug concentrations and the value of measuring TKI tumor- over plasma-concentrations. The finding that reaching higher tumor drug concentrations provides most clinical benefit in patients with treatment refractory malignancies indicates that the inhibitory potency of sunitinib may be enforced by a high-dose intermittent treatment schedule. These results provide proof of concept for testing other clinically available multitargeted tyrosine kinase inhibitors in a high-dose intermittent treatment schedule. Full article
(This article belongs to the Special Issue Tyrosine Kinase Inhibitors (TKIs) in Cancer Targeted Therapy)
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22 pages, 3665 KiB  
Communication
Preliminary Discovery of Small Molecule Inhibitors of Epidermal Growth Factor Receptor (EGFR) That Bind to the Extracellular Domain
by Rosa Di Liddo, Marco Verona, Christian Vaccarin, Laura Acquasaliente, Sandra Schrenk, Monica Piccione, Carola Cenzi, Michele De Franco, Matteo Dal Prà, Giovanni Ribaudo, Maria Grazia Ferlin, Maria Teresa Conconi, Adriana Chilin, Valentina Gandin and Giovanni Marzaro
Cancers 2022, 14(15), 3647; https://doi.org/10.3390/cancers14153647 - 27 Jul 2022
Cited by 3 | Viewed by 2852
Abstract
The Epidermal Growth Factor Receptor (EGFR) is a transmembrane glycoprotein belonging to the protein kinase superfamily. It is composed of an extracellular domain, a transmembrane anchoring region and a cytoplasmic region endowed with tyrosine kinase activity. Genetic mutations of EGFR kinase cause higher [...] Read more.
The Epidermal Growth Factor Receptor (EGFR) is a transmembrane glycoprotein belonging to the protein kinase superfamily. It is composed of an extracellular domain, a transmembrane anchoring region and a cytoplasmic region endowed with tyrosine kinase activity. Genetic mutations of EGFR kinase cause higher activity thereby stimulating downstream signaling pathways that, in turn, impact transcription and cell cycle progression. Due to the involvement of mutant EGFR in tumors and inflammatory diseases, in the past decade, several EGFR inhibitory strategies have been extensively studied, either targeting the extracellular domain (through monoclonal antibodies) or the intracellular kinase domain (through ATP-mimic small molecules). Monoclonal antibodies impair the binding to growth factor, the receptor dimerization, and its activation, whereas small molecules block the intracellular catalytic activity. Herein, we describe the development of a novel small molecule, called DSF-102, that interacts with the extracellular domain of EGFR. When tested in vitro in KRAS mutant A549 cells, it impairs EGFR activity by exerting (i) dose-dependent toxicity effects; (ii) a negative regulation of ERK, MAPK p38 and AKT; and (iii) a modulation of the intracellular trafficking and lysosomal degradation of EGFR. Interestingly, DSF-102 exerts its EGFR inhibitory activity without showing interaction with the intracellular kinase domain. Taken together, these findings suggest that DSF-102 is a promising hit compound for the development of a novel class of anti-EGFR compounds, i.e., small molecules able to interact with the extracellular domain of EGFR and useful for overcoming the KRAS-driven resistance to TKI treatment. Full article
(This article belongs to the Special Issue Tyrosine Kinase Inhibitors (TKIs) in Cancer Targeted Therapy)
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Graphical abstract

11 pages, 1984 KiB  
Article
Cosuppression of NF-κB and AICDA Overcomes Acquired EGFR-TKI Resistance in Non-Small Cell Lung Cancer
by Min-Kyung Yeo, Yoonjoo Kim, Da Hye Lee, Chaeuk Chung and Go Eun Bae
Cancers 2022, 14(12), 2940; https://doi.org/10.3390/cancers14122940 - 14 Jun 2022
Cited by 5 | Viewed by 1832
Abstract
Background: Acquired resistance after EGFR-tyrosine kinase inhibitor (TKI) treatment is the rule rather than the exception. Overcoming resistance to EGFR-TKIs is essential if we are to develop better therapeutic strategies for lung cancer patients. Here, we examine the effector signaling pathways underlying TKI [...] Read more.
Background: Acquired resistance after EGFR-tyrosine kinase inhibitor (TKI) treatment is the rule rather than the exception. Overcoming resistance to EGFR-TKIs is essential if we are to develop better therapeutic strategies for lung cancer patients. Here, we examine the effector signaling pathways underlying TKI resistance and propose targets to overcome the resistance of lung adenocarcinoma (LAC) to TKI. Methods: We compared the expression of NF-κB, AICDA, Akt, IL-6, Jak2, and Stat3 by EGFR-TKI-resistant and EGFR-TKI-sensitive LAC cell lines, and by LAC patients treated with EGFR-TKIs; we then evaluated links between expression and treatment responses. We also examined the therapeutic effects of NF-κB and AICDA inhibition in EGFR-TKI-resistant LACs. Results: NF-κB and AICDA were more expressed by EGFR-TKI-resistant LACs than by EGFR-TKI-sensitive LACs. EGFR-TKIs induced a dose-dependent increase in the expression of NF-κB, AICDA, and IL-6. Inhibition of NF-κB suppressed the expression of AICDA, Akt, and IL-6 in EGFR-TKI-resistant and EGFR-TKI-sensitive LACs, whereas knockdown of AICDA suppressed the expression of NF-κB and Akt in both cell types. Treating EGFR-TKI-resistant LACs with an EGFR-TKI, alongside cosuppression of NF-κB and AICDA, had a significant therapeutic effect. Conclusion: Treatment with an EGFR-TKI plus cosuppression of NF-κB and AICDA may be a promising strategy to overcome EGFR-TKI resistance in LACs. Full article
(This article belongs to the Special Issue Tyrosine Kinase Inhibitors (TKIs) in Cancer Targeted Therapy)
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