Targeted Therapies in Cancer: To Be or Not to Be, Selective

Abstract

Development of targeted therapies in recent years revealed several nonchemotherapeutic options for patients. Chief among targeted therapies is small molecule kinase inhibitors targeting key oncogenic signaling proteins. Through competitive and noncompetitive inhibition of these kinases, and therefore the pathways they activate, cancers can be slowed or completely eradicated, leading to partial or complete remissions for many cancer types. Unfortunately, for many patients, resistance to targeted therapies, such as kinase inhibitors, ultimately develops and can necessitate multiple lines of treatment. Drug resistance can either be de novo or acquired after months or years of drug exposure. Since resistance can be due to several unique mechanisms, there is no one-size-fits-all solution to this problem. However, combinations that target complimentary pathways or potential escape mechanisms appear to be more effective than sequential therapy. Combinations of single kinase inhibitors or alternately multikinase inhibitor drugs could be used to achieve this goal. Understanding how to efficiently target cancer cells and overcome resistance to prior lines of therapy became imperative to the success of cancer treatment. Due to the complexity of cancer, effective treatment options in the future will likely require mixing and matching these approaches in different cancer types and different disease stages.

Pharmacological PP2A reactivation overcomes multikinase inhibitor tolerance across brain tumor cell models

“…MKIs provide an attractive approach to simultaneously inhibit several oncogenic kinases, and some MKIs (e.g., Sunitinib, PKC412), are clinically used as cancer therapies. 48 However, similar to more selective kinase inhibitors, all tested MKIs have thus far failed in GB clinical trials. 4 To better understand GB relevant STS target kinases, we developed the AToMI approach 24 and found several kinases which synergized with PP2A reactivation by either PME-1 inhibition or by SMAPs.…”

Novel 2-(5-Aryl-4,5-Dihydropyrazol-1-yl)thiazol-4-One as EGFR Inhibitors: Synthesis, Biological Assessment and Molecular Docking Insights

“…The emergence of targeted therapies specifically the signaling-pathways-targeting chemotherapeutic agents construct a new era of selective chemotherapeutic hits that could attack cancer cells and/or the tumor microenvironment responsible for tumor proliferation, resulting in greater efficacy and minor side effects on normal cells. 6 , 7 One of the most principal signaling pathways was the tyrosine kinase (TK) Epidermal Growth Factor Receptor (EGFR) that regulates several cell functions which include cell growth, survival, multiplication, differentiation, and apoptosis. The EGFR is activated as a result of conformational changes caused by binding interactions of the endogenous EGF ligand within EGFR extracellular binding domain.…”

Development of Actionable Targets of Multi-kinase Inhibitors (AToMI) screening platform to dissect kinase targets of staurosporines in glioblastoma cells

“…Recent studies demonstrate that only a few kinase inhibitors target selectively their intended kinase target, and that the therapeutic effects of many kinase inhibitors are mediated by inhibition of other than their assumed target kinase (10,11). The unselectivity of kinase inhibitors can be employed therapeutically in a case the multi-kinase inhibitor (MKI) (12). Of clinically approved MKIs, sunitinib has an FDA approval for the treatment of gastrointestinal stromal tumors and advanced renal cell carcinoma.…”

“…Additionally, derivatives of the classical MKI staurosporine (STS), have reached the clinics. Midostaurin (PKC412) is approved for the treatment of FLT3-mutated acute myeloid leukemia (12), whereas another STS derivative UCN-01 (7-hydroxystaurosporine), was tested in phase II clinical trials in metastatic melanoma and relapsed T-Cell Lymphomas (NCT00082017). However, it is well established that each of these clinically tested STS derivatives inhibit activities of up to 50 kinases with approximately similar efficiency (10,13,14).…”

“…Regardless of their very wide target spectrum and reputation as “dirty kinase inhibitor” several STS derivatives have reached or has been tested in the clinics. Midostaurin (PKC412) is approved for the treatment of FLT3-mutated acute myeloid leukemia (Montoya et al ., 2021), whereas another STS derivative UCN-01 (7-hydroxystaurosporine) was tested in phase II clinical trials in metastatic melanoma and relapsed T-Cell Lymphomas (NCT00082017). However, in most cases it is not well established what are the actual kinase inhibitor targets the inhibition of which mediates the therapeutic effects in different indications.…”