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4 pages, 181 KiB

Open AccessEditorial

Special Issue: Resistance to Targeted Therapies in Human Cancer

by Tae-Won Lee, Hee-Joo Choi, Kyung-Min Lee and Jeong-Yeon Lee

Biomedicines 2023, 11(2), 414; https://doi.org/10.3390/biomedicines11020414 - 31 Jan 2023

Viewed by 1010

Abstract

Cancer is the second leading cause of death worldwide, accounting for approximately 10 million deaths in 2020 [...] Full article

(This article belongs to the Special Issue Resistance to Targeted Therapies in Human Cancer)

Research

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20 pages, 4438 KiB

Open AccessArticle

An In Vivo Inflammatory Loop Potentiates KRAS Blockade

by Kristina A. M. Arendt, Giannoula Ntaliarda, Vasileios Armenis, Danai Kati, Christin Henning, Georgia A. Giotopoulou, Mario A. A. Pepe, Laura V. Klotz, Anne-Sophie Lamort, Rudolf A. Hatz, Sebastian Kobold, Andrea C. Schamberger and Georgios T. Stathopoulos

Biomedicines 2022, 10(3), 592; https://doi.org/10.3390/biomedicines10030592 - 03 Mar 2022

Cited by 4 | Viewed by 2800

Abstract

KRAS (KRAS proto-oncogene, GTPase) inhibitors perform less well than other targeted drugs in vitro and fail clinical trials. To investigate a possible reason for this, we treated human and murine tumor cells with KRAS inhibitors deltarasin (targeting phosphodiesterase-δ), cysmethynil (targeting isoprenylcysteine carboxylmethyltransferase), and [...] Read more.

KRAS (KRAS proto-oncogene, GTPase) inhibitors perform less well than other targeted drugs in vitro and fail clinical trials. To investigate a possible reason for this, we treated human and murine tumor cells with KRAS inhibitors deltarasin (targeting phosphodiesterase-δ), cysmethynil (targeting isoprenylcysteine carboxylmethyltransferase), and AA12 (targeting KRAS^G12C), and silenced/overexpressed mutant KRAS using custom-designed vectors. We showed that KRAS-mutant tumor cells exclusively respond to KRAS blockade in vivo, because the oncogene co-opts host myeloid cells via a C-C-motif chemokine ligand 2 (CCL2)/interleukin-1 beta (IL-1β)-mediated signaling loop for sustained tumorigenicity. Indeed, KRAS-mutant tumors did not respond to deltarasin in C-C motif chemokine receptor 2 (Ccr2) and Il1b gene-deficient mice, but were deltarasin-sensitive in wild-type and Ccr2-deficient mice adoptively transplanted with wild-type murine bone marrow. A KRAS-dependent pro-inflammatory transcriptome was prominent in human cancers with high KRAS mutation prevalence and poor predicted survival. Our findings support that in vitro cellular systems are suboptimal for anti-KRAS drug screens, as these drugs function to suppress interleukin-1 receptor 1 (IL1R1) expression and myeloid IL-1β-delivered pro-growth effects in vivo. Moreover, the findings support that IL-1β blockade might be suitable for therapy for KRAS-mutant cancers. Full article

(This article belongs to the Special Issue Resistance to Targeted Therapies in Human Cancer)

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17 pages, 4620 KiB

Open AccessArticle

Development of Small-Molecule STING Activators for Cancer Immunotherapy

by Hee Ra Jung, Seongman Jo, Min Jae Jeon, Hyelim Lee, Yeonjeong Chu, Jeehee Lee, Eunha Kim, Gyu Yong Song, Cheulhee Jung, Hyejin Kim and Sanghee Lee

Biomedicines 2022, 10(1), 33; https://doi.org/10.3390/biomedicines10010033 - 24 Dec 2021

Cited by 8 | Viewed by 4087

Abstract

In cancer immunotherapy, the cyclic GMP–AMP synthase–stimulator of interferon genes (STING) pathway is an attractive target for switching the tumor immunophenotype from ‘cold’ to ‘hot’ through the activation of the type I interferon response. To develop a new chemical entity for STING activator [...] Read more.

In cancer immunotherapy, the cyclic GMP–AMP synthase–stimulator of interferon genes (STING) pathway is an attractive target for switching the tumor immunophenotype from ‘cold’ to ‘hot’ through the activation of the type I interferon response. To develop a new chemical entity for STING activator to improve cyclic GMP-AMP (cGAMP)-induced innate immune response, we identified KAS-08 via the structural modification of DW2282, which was previously reported as an anti-cancer agent with an unknown mechanism. Further investigation revealed that direct STING binding or the enhanced phosphorylation of STING and downstream effectors were responsible for DW2282-or KAS-08-mediated STING activity. Furthermore, KAS-08 was validated as an effective STING pathway activator in vitro and in vivo. The synergistic effect of cGAMP-mediated immunity and efficient anti-cancer effects successfully demonstrated the therapeutic potential of KAS-08 for combination therapy in cancer treatment. Full article

(This article belongs to the Special Issue Resistance to Targeted Therapies in Human Cancer)

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20 pages, 3688 KiB

Open AccessArticle

Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML)

by Hanane Djamai, Jeannig Berrou, Mélanie Dupont, Marie-Magdelaine Coudé, Marc Delord, Emmanuelle Clappier, Alice Marceau-Renaut, Anna Kaci, Emmanuel Raffoux, Raphaël Itzykson, Caroline Berthier, Hsin-Chieh Wu, Rita Hleihel, Ali Bazarbachi, Hugues de Thé, André Baruchel, Claude Gardin, Hervé Dombret and Thorsten Braun

Biomedicines 2021, 9(11), 1704; https://doi.org/10.3390/biomedicines9111704 - 17 Nov 2021

Cited by 4 | Viewed by 2434

Abstract

BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including NPM1c AML cells. Nevertheless, the biological consequences of BETi in NPM1c AML were not fully investigated. Even if of better prognosis AML patients with NPM1c may relapse and treatment remains difficult. [...] Read more.

BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including NPM1c AML cells. Nevertheless, the biological consequences of BETi in NPM1c AML were not fully investigated. Even if of better prognosis AML patients with NPM1c may relapse and treatment remains difficult. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) demonstrated activity in NPM1c AML. We found that BETi, similar to ATO + ATRA, induced differentiation and apoptosis which was TP53 independent in the NPM1c cell line OCI-AML3 and primary cells. Furthermore, BETi induced proteasome-dependent degradation of NPM1c. BETi degraded NPM1c in the cytosol while BRD4 is degraded in the nucleus which suggests that restoration of the NPM1/BRD4 equilibrium in the nucleus of NPM1c cells is essential for the efficacy of BETi. While ATO + ATRA had significant biological activity in NPM1c IMS-M2 cell line, those cells were resistant to BETi. Gene profiling revealed that IMS-M2 cells probably resist to BETi by upregulation of LSC pathways independently of the downregulation of a core BET-responsive transcriptional program. ATO + ATRA downregulated a NPM1c specific HOX gene signature while anti-leukemic effects of BETi appear HOX gene independent. Our preclinical results encourage clinical testing of BETi in NPM1c AML patients. Full article

(This article belongs to the Special Issue Resistance to Targeted Therapies in Human Cancer)

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14 pages, 3797 KiB

Open AccessArticle

Antiangiogenic Properties of Axitinib versus Sorafenib Following Sunitinib Resistance in Human Endothelial Cells—A View towards Second Line Renal Cell Carcinoma Treatment

by Eva Juengel, Pascal Schnalke, Jochen Rutz, Sebastian Maxeiner, Felix K.-H. Chun and Roman A. Blaheta

Biomedicines 2021, 9(11), 1630; https://doi.org/10.3390/biomedicines9111630 - 06 Nov 2021

Cited by 3 | Viewed by 1912

Abstract

Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors predominate as first-line therapy options for renal cell carcinoma. When first-line TKI therapy fails due to resistance development, an optimal second-line therapy has not yet been established. The present investigation is directed towards comparing the [...] Read more.

Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors predominate as first-line therapy options for renal cell carcinoma. When first-line TKI therapy fails due to resistance development, an optimal second-line therapy has not yet been established. The present investigation is directed towards comparing the anti-angiogenic properties of the TKIs, sorafenib and axitinib on human endothelial cells (HUVECs) with acquired resistance towards the TKI sunitinib. HUVECs were driven to resistance by continuously exposing them to sunitinib for six weeks. They were then switched to a 24 h or further six weeks treatment with sorafenib or axitinib. HUVEC growth, as well as angiogenesis (tube formation and scratch wound assay), were evaluated. Cell cycle proteins of the CDK-cyclin axis (CDK1 and 2, total and phosphorylated, cyclin A and B) and the mTOR pathway (AKT, total and phosphorylated) were also assessed. Axitinib (but not sorafenib) significantly suppressed growth of sunitinib-resistant HUVECs when they were exposed for six weeks. This axinitib-associated growth reduction was accompanied by a cell cycle block at the G0/G1-phase. Both axitinib and sorafenib reduced HUVEC tube length and prevented wound closure (sorafenib > axitinib) when applied to sunitinib-resistant HUVECs for six weeks. Protein analysis revealed diminished phosphorylation of CDK1, CDK2 and pAKT, accompanied by a suppression of cyclin A and B. Both drugs modulated CDK-cyclin and AKT-dependent signaling, associated either with both HUVEC growth and angiogenesis (axitinib) or angiogenesis alone (sorafenib). Axitinib and sorafenib may be equally applicable as second line treatment options, following sunitinib resistance. Full article

(This article belongs to the Special Issue Resistance to Targeted Therapies in Human Cancer)

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22 pages, 10451 KiB

Open AccessArticle

Rutaecarpine Increases Anticancer Drug Sensitivity in Drug-Resistant Cells through MARCH8-Dependent ABCB1 Degradation

by Tingting Zou, Cheng Zeng, Junyan Qu, Xiaohua Yan and Zhenghong Lin

Biomedicines 2021, 9(9), 1143; https://doi.org/10.3390/biomedicines9091143 - 02 Sep 2021

Cited by 12 | Viewed by 2460

Abstract

The overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) subfamily B member 1 (ABCB1; P-glycoprotein; MDR1) in some types of cancer cells is one of the mechanisms responsible for the development of multidrug resistance (MDR), which leads to the failure of chemotherapy. Therefore, it [...] Read more.

The overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) subfamily B member 1 (ABCB1; P-glycoprotein; MDR1) in some types of cancer cells is one of the mechanisms responsible for the development of multidrug resistance (MDR), which leads to the failure of chemotherapy. Therefore, it is important to inhibit the activity or reduce the expression level of ABCB1 to maintain an effective intracellular level of chemotherapeutic drugs. In this study, we found that rutaecarpine, a bioactive alkaloid isolated from Evodia Rutaecarpa, has the capacity to reverse ABCB1-mediated MDR. Our data indicated that the reversal effect of rutaecarpine was related to the attenuation of the protein level of ABCB1. Mechanistically, we demonstrated that ABCB1 is a newly discovered substrate of E3 ubiquitin ligase membrane-associated RING-CH 8 (MARCH8). MARCH8 can interact with ABCB1 and promote its ubiquitination and degradation. In short, rutaecarpine increased the degradation of ABCB1 protein by upregulating the protein level of MARCH8, thereby antagonizing ABCB1-mediated MDR. Notably, the treatment of rutaecarpine combined with other anticancer drugs exhibits a therapeutic effect on transplanted tumors. Therefore, our study provides a potential chemotherapeutic strategy of co-administrating rutaecarpine with other conventional chemotherapeutic agents to overcome MDR and improve therapeutic effect. Full article

(This article belongs to the Special Issue Resistance to Targeted Therapies in Human Cancer)

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Review

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16 pages, 853 KiB

Open AccessReview

Targeted Protein Degradation to Overcome Resistance in Cancer Therapies: PROTAC and N-Degron Pathway

by Hanbyeol Kim, Jeongbae Park and Jeong-Mok Kim

Biomedicines 2022, 10(9), 2100; https://doi.org/10.3390/biomedicines10092100 - 27 Aug 2022

Cited by 5 | Viewed by 4198

Abstract

Extensive progress in understanding the molecular mechanisms of cancer growth and proliferation has led to the remarkable development of drugs that target cancer-driving molecules. Most target molecules are proteins such as kinases and kinase-associated receptors, which have enzymatic activities needed for the signaling [...] Read more.

Extensive progress in understanding the molecular mechanisms of cancer growth and proliferation has led to the remarkable development of drugs that target cancer-driving molecules. Most target molecules are proteins such as kinases and kinase-associated receptors, which have enzymatic activities needed for the signaling cascades of cells. The small molecule inhibitors for these target molecules greatly improved therapeutic efficacy and lowered the systemic toxicity in cancer therapies. However, long-term and high-dosage treatment of small inhibitors for cancer has produced other obstacles, such as resistance to inhibitors. Among recent approaches to overcoming drug resistance to cancers, targeted protein degradation (TPD) such as proteolysis-targeting chimera (PROTAC) technology adopts a distinct mechanism of action by which a target protein is destroyed through the cellular proteolytic system, such as the ubiquitin–proteasome system or autophagy. Here, we review the currently developed PROTACs as the representative TPD molecules for cancer therapy and the N-degrons of the N-degron pathways as the potential TPD ligands. Full article

(This article belongs to the Special Issue Resistance to Targeted Therapies in Human Cancer)

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17 pages, 950 KiB

Open AccessReview

Immune Checkpoint Blockades in Triple-Negative Breast Cancer: Current State and Molecular Mechanisms of Resistance

by Hyungjoo Kim, Je-Min Choi and Kyung-min Lee

Biomedicines 2022, 10(5), 1130; https://doi.org/10.3390/biomedicines10051130 - 13 May 2022

Cited by 12 | Viewed by 3660

Abstract

Immune checkpoint blockades (ICBs) have revolutionized cancer treatment. Recent studies have revealed a subset of triple-negative breast cancer (TNBC) to be considered as an immunogenic breast cancer subtype. Characteristics of TNBC, such as higher mutation rates and number of tumor-infiltrating immune cells, render [...] Read more.

Immune checkpoint blockades (ICBs) have revolutionized cancer treatment. Recent studies have revealed a subset of triple-negative breast cancer (TNBC) to be considered as an immunogenic breast cancer subtype. Characteristics of TNBC, such as higher mutation rates and number of tumor-infiltrating immune cells, render the immunogenic phenotypes. Consequently, TNBCs have shown durable responses to ICBs such as atezolizumab and pembrolizumab in clinic. However, a significant number of TNBC patients do not benefit from these therapies, and mechanisms of resistance are poorly understood. Here, we review biomarkers that predict the responsiveness of TNBCs to ICB and recent advances in delineating molecular mechanisms of resistance to ICBs. Full article

(This article belongs to the Special Issue Resistance to Targeted Therapies in Human Cancer)

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25 pages, 6925 KiB

Open AccessReview

Overcoming Therapy Resistance and Relapse in TNBC: Emerging Technologies to Target Breast Cancer-Associated Fibroblasts

by Farhana Mollah and Pegah Varamini

Biomedicines 2021, 9(12), 1921; https://doi.org/10.3390/biomedicines9121921 - 15 Dec 2021

Cited by 10 | Viewed by 4010

Abstract

Breast cancer is the most diagnosed cancer and is the leading cause of cancer mortality in women. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer. Often, TNBC is not effectively treated due to the lack of specificity of conventional therapies [...] Read more.

Breast cancer is the most diagnosed cancer and is the leading cause of cancer mortality in women. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer. Often, TNBC is not effectively treated due to the lack of specificity of conventional therapies and results in relapse and metastasis. Breast cancer-associated fibroblasts (BCAFs) are the predominant cells that reside in the tumor microenvironment (TME) and regulate tumorigenesis, progression and metastasis, and therapy resistance. BCAFs secrete a wide range of factors, including growth factors, chemokines, and cytokines, some of which have been proved to lead to a poor prognosis and clinical outcomes. This TME component has been emerging as a promising target due to its crucial role in cancer progression and chemotherapy resistance. A number of therapeutic candidates are designed to effectively target BCAFs with a focus on their tumor-promoting properties and tumor immune response. This review explores various agents targeting BCAFs in TNBC, including small molecules, nucleic acid-based agents, antibodies, proteins, and finally, nanoparticles. Full article

(This article belongs to the Special Issue Resistance to Targeted Therapies in Human Cancer)

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20 pages, 10411 KiB

Open AccessReview

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

by Skye Montoya, Deborah Soong, Nina Nguyen, Maurizio Affer, Sailasya P. Munamarty and Justin Taylor

Biomedicines 2021, 9(11), 1591; https://doi.org/10.3390/biomedicines9111591 - 01 Nov 2021

Cited by 15 | Viewed by 3354

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Resistance to Targeted Therapies in Human Cancer)

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