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Treatments and Challenges
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
Despite their targeted activity, multiple mechanisms of feedback inhibition and kinase crosstalk exist in almost every kinase-signaling network. In cancer treatment, adaptations of the kinome (i.e., protein kinase superfamily) may eventually lead to treatment failure [1169–1171]. Studies report that tumor cells hijack pathway redundancy and feedback routes, as well as crosstalk, by adapting cellular signaling circuitry as a response to chronic drug treatment to maintain their functions and survival [1169]. Hence, small-molecule inhibitor drugs targeting receptor tyrosine kinases when used as single agents cause tumor shrinkage, but not complete elimination [1170]. The lingering tumor cells (i.e., residual disease) can act as the platform from which acquired treatment resistance emerges [1170]. Acquired resistance to kinase inhibitors often occurs and most patients eventually relapse [1172]. Resistance follows either from an adaptive multifactorial process, where signaling pathways are remodeled to relieve the effects of (kinase) inhibition, or from longer-term processes (i.e., gradual adaptation), where tumor cells acquire mutations or gene copy number modifications that bestow a selective advantage (i.e., inhibitor-specific selective pressures) to mitigate the negative effects of treatment [374, 1172, 1173]. There are other published reviews that provide detailed information on kinase inhibitors, and the reader is referred to these reviews [1174–1177].
Cancer
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Elyce Cardonick, Charlotte Maggen, Puja Patel
Treatment of severe leukocytosis is necessary to reduce maternal risk of stroke hypoxia, deep venous thrombosis (DVT). There are case reports of observation alone during pregnancy in patients without splenomegaly. Leukophoresis can be a temporizing measure to reduce WBC and spleen size if necessary [85]. Tyrosine kinase inhibitors such as imatinib, the newest advance in the treatment of chronic leukemia in non-pregnant adults, has been shown to cause teratogenic effects in rats, including exencephaly or encephalocele and absent or reduced frontal and absent parietal bones. If a pregnant patient newly diagnosed with CML is symptomatic with splenomegaly, with no clinical response to leukapheresis or other medications and is beyond the first trimester, imatinib would be preferred over second generation tyrosine kinase inhibitors such as dasatinib or nilotinib. Reports show imatinib is 95% bound to plasma proteins with a molecular weight of 590 which suggests low placental transfer. Case reports of tyrosine kinase inhibitor imatinib during pregnancy beyond the first trimester have been reassuring with prompt responses in pregnancy [86–89].
Thyroid cancer
Published in Nadia Barghouthi, Jessica Perini, Endocrine Diseases in Pregnancy and the Postpartum Period, 2021
While there are several Food and Drug Administration (FDA)-approved drugs or combinations of systemic therapy to treat advanced thyroid cancer, such as tyrosine kinase inhibitors (TKI), selective BRAF V600E kinase, and MEK1/2 kinase inhibitors, these medications are either not studied fully in pregnancy or are known to cause fetal harm. If considering initiation during pregnancy, women should be counseled about potential fetal adverse effects. If treatment is required postpartum, effective contraceptive methods are recommended.
Evaluation of multikinase inhibitor LDN193189 induced hepatotoxicity in teleost fish Poecilia latipinna
Published in Drug and Chemical Toxicology, 2019
Isha Ranadive, Sonam Patel, Abhilasha Mhaske, Gowri Kumari Uggini, Isha Desai, Suresh Balakrishnan
The use of kinase inhibitor as a prospective drug in combating cancers of diverse type, at least on an experimental scale, is gaining momentum. Dasatinib, a multikinase inhibitor targeting BCR/ABL and Src tyrosine kinases, blocks epithelial ovarian cancer (EOC) cell invasion and induces apoptosis (Konecny et al.2009). Recently, McDermott et al. (2017) have found that CDK8 inhibition by CDK8/19-selective small molecule kinase inhibitors, via shRNA knockdown or CRISPR/CAS9 knockout suppresses estrogen-induced transcription in ER-positive breast cancer cells and hence can be beneficial for breast cancer therapy. Targeting kinases, therefore, have proven to be very useful as primary or adjuvant anticancer treatments. Therefore, small molecule inhibitors that affect multiple receptor kinases are being cited as a novel therapeutics for cancer (Zhang et al.2009).
Bidirectional Adaptive Signaling between cancer and stromal cells: mechanisms and therapeutics
Published in Expert Review of Proteomics, 2018
M. Boutchueng-Djidjou, Uwe Rix, Eric B. Haura
Drug resistance is a major obstacle toward the cure of cancer. Despite the development of potent tyrosine kinase inhibitors (TKIs), sequential therapy with newer generations of EGFR and ALK inhibitors in lung cancer is almost inevitably met with different resistance mechanisms [1]. Kinase inhibitors do not only eradicate cellular signaling, but they rather trigger adaptive signaling responses in cancer cells [2]. They engage off-targets not only in the cancer cells but also in surrounding stroma leading to a highly dynamic, and drug-specific adaptive signaling response of the cancer cell/stroma system [3]. The fibroblasts are an important component of the tumor microenvironment (TME). Cancer cells and the surrounding cancer associated fibroblasts communicate in a bi-directional way, whereby, cancer cells educate the fibroblasts for the acquisition of new cancer associated phenotypes (CAFs) and the CAFs feed them back by inducing an epigenetic reprogramming or signal rewiring before, during, and after drug treatment [4]. CAFs secrete extracellular matrix proteins, chemokines, and growth factors which regulate the signaling of adjacent cells of the TME [5] and the responses of cancer cells after drug treatment [6]. These events likely contribute to the functional relevance of the small drug-tolerant ‘persister’ cell populations in the long-term development of TKIs-resistant cancer cells [7]. Because the simple elimination of CAFs can be detrimental [8], it is worth to redefine strategies leading to CAF reprogramming by rewiring their tumor-supporting signaling networks.
The importance of the initial response to cancer treatment in predicting longer overall survival
Published in Expert Review of Clinical Pharmacology, 2018
Caroline E. McCoach, Robert C. Doebele
With the growing list of cancer treatment options, it is important to consider the validity of DepOR not only across tumor types but also across different therapeutic mechanisms of action. Tumor response to treatment can be via direct mechanisms such as by cytotoxic chemotherapies that cause cell death by damaging DNA or preventing formation of nucleic acids. Alternatively, targeted therapies are a large subcategory with numerous mechanisms of action. In the studies discussed here, kinase inhibitors are small molecule inhibitors that block growth and development signaling pathways, leading to cell death. Immunotherapies are a third broad therapeutic category that work less directly. Anti-cytotoxic T lymphocyte associated protein 4 (CTLA-4) or anti-programmed cell death-1 antibodies (PD-1) function by enhancing immune activation and T-cell proliferation. In addition, unlike chemotherapy and most targeted therapies, this treatment may not immediately translate to tumor cell death and the treatment effect may persist, even after cessation of treatment. Finally, biologic agents like cetuximab and bevacizumab work by activating antibody-dependent cellular cytotoxicity and complement mediated cytotoxicity in addition to direct antiproliferative effects. Each of these mechanisms result in different tempos of cell death. Given this, it is important to consider whether DepOR metric can be used to evaluate treatment response in therapies with different mechanisms of action.