Treatment Of Drug-resistant Cancer Research Articles

Molecular basis for antibody recognition of multiple drug–peptide/MHC complexes

The HapImmuneTM platform exploits covalent inhibitors as haptens for creating major histocompatibility complex (MHC)-presented tumor-specific neoantigens by design, combining targeted therapies with immunotherapy for the treatment of drug-resistant cancers. A HapImmune antibody, R023, recognizes multiple sotorasib-conjugated KRAS(G12C) peptides presented by different human leukocyte antigens (HLAs). This high specificity to sotorasib, coupled with broad HLA-binding capability, enables such antibodies, when reformatted as T cell engagers, to potently and selectively kill sotorasib-resistant KRAS(G12C) cancer cells expressing different HLAs upon sotorasib treatment. The loosening of HLA restriction could increase the patient population that can benefit from this therapeutic approach. To understand the molecular basis for its unconventional binding capability, we used single-particle cryogenic electron microscopy to determine the structures of R023 bound to multiple sotorasib-peptide conjugates presented by different HLAs. R023 forms a pocket for sotorasib between the VH and VL domains, binds HLAs in an unconventional, angled way, with VL making most contacts with them, and makes few contacts with the peptide moieties. This binding mode enables the antibody to accommodate different hapten-peptide conjugates and to adjust its conformation to different HLAs presenting hapten-peptides. Deep mutational scanning validated the structures and revealed distinct levels of mutation tolerance by sotorasib- and HLA-binding residues. Together, our structural information and sequence landscape analysis reveal key features for achieving MHC-restricted recognition of multiple hapten-peptide antigens, which will inform the development of next-generation therapeutic antibodies.

Abstract 4755: Extracellular GRP78 inhibition reverses drug and immune resistance in cancer cells

Abstract CBT300 was created from Creative BioTherapeutics’ discovery that drug resistant recurrent cancer cells up-regulate a survival pathway that results in the expression of extracellular Glucose-Regulated Protein 78 (ecGRP78) in the tumor microenvironment (TME). This TME ecGRP78 binds to cancer and immune cell surfaces, which induces a cascade of events to increase drug resistance, immune suppression, and cancer stem cell (CSC) formation. CBT300 targets surface bound ecGRP78 that has been found on breast, lung, ovarian, prostate, melanoma, multiple myeloma, colon, pediatric and adult brain tumors. We can now show that inhibition of ecGRP78 can a) induce apoptosis of drug resistant tumor cells, b) eliminate drug and immune resistance showing synergistic effects with chemotherapy and immunotherapy, c) decrease the amount of chemotherapy about 90% in combination with CBT300. Recent publications show that ecGRP78 is found on many types of tumor cell surfaces but not on normal cell surfaces. In fact, cell surface bound ecGRP78 is important for many aspects of cancer development, including cell survival, proliferation, chemoresistance, angiogenesis, metastasis formation, immune suppression, and stem cell formation. Recently, it has been shown that increased ecGRP78 expression in metastatic breast cancer, glioblastoma and multiple myeloma patients was significantly associated with later stage, increased distant metastasis, increased aggressiveness, shorter disease-free survival, and decreased overall survival. In studies to help understand how ecGRP78 causes tumor progression and drug and immune resistance, we discovered a novel ecGRP78 binding transmembrane protein on TNBC, and brain cancer cells called Receptor Tyrosine Kinase Orphan Receptor-1 (ROR1). Using the GRP78 binding domain from ROR1 and a human Fc domain, we created a biologic fusion protein that is a potent and specific ecGRP78 inhibitor called CBT300. We now show that CBT300’s elimination of csGRP78 destabilizes and removes oncofetal proteins ROR1, and Cripto, and checkpoint protein PD-L1 from tumor cell surfaces resulting in reversal of chemoresistance, reduction in immune suppression, inhibition of stem cell phenotype and increased tumor cell apoptosis. Our results with CBT300 demonstrate proof of concept data in vitro and in vivo for our novel ecGRP78 inhibitor on several drug resistant cancers demonstrating the potential to provide a major advance in the treatment of drug resistant cancers either alone or in combination with lower doses of chemotherapy. Exploiting a novel mechanism of action with a non-toxic, efficacious and cost effective biologic therapy that has shown increased survival in recurrent cancers will bring new hope for these patients. Citation Format: Donald J. Davidson, Jorryn Zelek, Elizabeth Stolarik, Mariah Thigpen, Anita Davidson, DPT. Extracellular GRP78 inhibition reverses drug and immune resistance in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4755.

Research Progress of Plant-Derived Natural Products against Drug-Resistant Cancer.

As one of the malignant diseases globally, cancer seriously endangers human physical and mental health because of its high morbidity and mortality. Conventional cancer treatment strategies, such as surgical resection and chemoradiotherapy, are effective at the early stage of cancer but have limited efficacy for advanced cancer. Along with cancer progress and treatment, resistance develops gradually within the population of tumor cells. As a consequence, drug resistance become the major cause that leads to disease progression and poor clinical prognosis in some patients. The mechanisms of cancer drug resistance are quite complex and involve various molecular and cellular mechanisms. Therefore, exploring the mechanisms and finding specific targets are becoming imperative to overcome drug resistance. In recent years, plant-derived natural products have been evaluated as potential therapeutic candidates against cancer with drug resistance due to low side effects and high anticancer efficacy. A growing number of studies have shown that natural products can achieve superior antitumor effects through multiple signaling pathways. The mechanisms include regulation of multiple drug resistance (MDR)-related genes, inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, induction of autophagy, and blockade of the cell cycle. This paper reviews the molecular and cellular mechanisms of cancer drug resistance, as well as the therapeutic effects and mechanisms of plant-derived natural products against cancer drug resistance. It provides references for developing therapeutic medication for drug-resistant cancer treatment with high efficacy and low side effects.

Ferroptosis in the pathogenesis of brain tumors

The field of research on ferroptosis has seen an explosive growth in the past few years since the term was coined in 2012. This review highlights the current state of knowledge on the developmental mechanism of this unique mode of cell death, induced by iron-dependent phospholipid peroxidation, which is regulated by a variety of cellular metabolic events, including redox homeostasis. The xCT system, an amino acid antiporter that supports the synthesis of glutathione (GSH) and oxidation protection, is among these factors. The risk of iron accumulation in neurons, astrocytes, oligodendrocytes, microglia, and Schwann cells and the development of oxidative stress are discussed. Ferroptosis triggers a cascade of events including activation of inflammation, oxidation of neurotransmitters, impaired neuronal communication, myelin sheath degeneration, astrocyte dysregulation, dementia, and cell death. On the other hand, the exceptional vulnerability of cancer cells originating from the nervous tissue to ferroptosis is estimated. The evidence is given for the initiation of ferroptosis in tumor cells as a factor inhibiting the growth and promoting the death of these cells. Particular attention is paid to the pharmacological modulation of ferroptosis through its induction and inhibition for the treatment of drug-resistant cancers. The choice of targets for the induction of ferroptosis in cancer cells is discussed. Glutathione peroxidase 4 and xCT amino acid antiporter are recognized as the most preferred targets and the antitumor potential of their inhibition and side effects are evaluated.

Photoredox-catalyzed reaction as a powerful tool for rapid natural product Gem-dimethylation modification: discovery of potent anti-cancer agents with improved druggability

Tylophorine has diverse biological activities; however, the stability, solubility, and central nervous system toxicity have severely limited use of tylophorine. The gem-dimethyl group is an organic chemistry functional group that consists of two methyl groups bonded to the same carbon atom. This feature has gained significant attention in medicinal chemistry due to its unique properties and potential applications in drug design. We applied a new photoredox methodology to tylophorine modification, resulting in a series of gem-dimethyl tylophorine analogues. Among the analogues, compound 4b demonstrated promising activity against a wide range of tumor cell lines and exhibited significantly improved drug-like properties, including enhanced solubility and stability. Compound 4b showed an exceptional inhibitory effect (7.8 nM) against a C481S mutation-induced ibrutinib-resistant non-Hodgkin’s lymphoma cell line, as well as primary tumor cell lines obtained from patients. Importantly, compound 4b exhibited significantly reduced anti-proliferative activity against the normal cell line tested, indicating the potential for an enhanced therapeutic window for compound 4b. Based on these early-stage data, we believe that our study provides a solid foundation for the development of new therapeutic agents for potential drug-resistant cancer treatment in the near future.

Doxorubicin hydrochloride and L-arginine co-loaded nanovesicle for drug resistance reversal stimulated by near-infrared light

Drug resistance is accountable for the inadequate outcome of chemotherapy in clinics. The newly emerging role of nitric oxide (NO) to conquer drug resistance has been recognized as a potential strategy. However, it remains a great challenge to realize targeted delivery as well as accurate release of NO at desired sites. Herein, we developed a PEGylated indocyanine green (mPEG-ICG) integrated nanovesicle system (PIDA) to simultaneously load doxorubicin hydrochloride (DOX⋅HCl) and the NO donor L-arginine (L-Arg), which can produce NO triggered by NIR light irradiation and exert multimodal therapy to sensitize drug-resistant cancers. Upon 808 nm irradiation, the NO released from PIDA led to a decrease in mitochondrial membrane potential, an increase in ROS and significant ATP depletion in K562/ADR cells, thus inhibiting cell growth and resolving the problem of drug resistance. Consequently, the in vivo experiment on K562/ADR-bearing nude mice indicated that PIDA nanovesicles achieved significant anticancer efficacy with a tumor inhibition rate of 80.8%. Above all, PIDA nanovesicles offer guidance for designing nanoplatforms for drug-resistant cancer treatment.

Coptidis Rhizoma Suppresses Metastatic Behavior by Inhibiting TGF-β-Mediated Epithelial-Mesenchymal Transition in 5-FU-Resistant HCT116 Cells.

Colorectal cancer (CRC) is the second most lethal malignancy worldwide. The high mortality rate of CRC is largely due to cancer metastasis. Recently, suppressing epithelial-to-mesenchymal transition (EMT) has been considered a promising strategy for treating metastatic cancer, especially drug-resistant metastatic cancer. The present study aimed to evaluate the antimetastatic effect of Coptidis Rhizoma, as well as the potential underlying mechanisms, using a 5-fluorouracil-resistant colon tumor cell model (HCT116/R). Coptidis Rhizoma 30% ethanol extract (CRE) significantly inhibited HCT116/R cells migration and invasion. CRE effectively inhibited EMT in HCT116/R cells by upregulating the expression of an epithelial marker (E-cadherin) and downregulating the expression of mesenchymal markers (vimentin, Snail, and ZEB2) at both the protein and gene levels. Immunofluorescence assays also confirmed consistent patterns in the levels of E-cadherin and vimentin. In addition, the anti-EMT activity of CRE and its related effects were associated with the CRE-mediated suppression of the TGF-β pathway, as shown by changes in the levels of downstream molecules (phosphorylated Akt and p38), and inhibition of migration, invasion, and protein expression of TGF-β after treatment/cotreatment with a TGF-β inhibitor (SB431542). In conclusion, Coptidis Rhizoma exerts an antimetastatic effect, especially in the treatment of drug-resistant cancer, and the possible mechanisms are associated with inhibiting EMT via TGF-β signaling. Thus, Coptidis Rhizoma will likely become a potential therapeutic candidate for simultaneously mitigating drug resistance and metastasis in CRC.

In Situ Coassembly Induced Mitochondrial Aggregation Activated Drug-Resistant Tumor Treatment.

Macrocyclic supramolecular coassembly is the current research hotspot for tumor treatment. Herein, we report a multivalent supramolecular coassembly strategy, which not only acquires long-time phosphorescent labeling of mitochondrial aggregation but also strongly enhances chemotherapeutic efficiency against drug-resistant tumors. The mitochondrial aggregation depends on cucurbit[8]uril-mediated cross-linkage of the hyaluronic acid polymer grafted by 4-bromophenylpyridium and mitochondrion-targeting peptide (HABMitP) residing on the mitochondria, taking advantage of the 2:1 homoternary host-guest complexation between cucurbit[8]uril and 4-bromophenylpyridium with an extraordinary binding constant (6.24 × 1012 M-2). In cisplatin-resistant MCF-7 tumor cells, the assembly induced mitochondrial aggregation substantially enhances the antitumor efficiency of cisplatin, with the ratio of apoptotic cells increasing from 43% to 96% compared to treatment with cisplatin alone, and thoroughly inhibits tumor growth in vivo. This study provides a novel way for biological phosphorescent imaging and treatment of drug-resistant cancers.

Ketone-selenoesters as potential anticancer and multidrug resistance modulation agents in 2D and 3D ovarian and breast cancer in vitro models

Long-term treatment of cancer with chemotherapeutics leads to the development of resistant forms that reduce treatment options. The main associated mechanism is the overexpression of transport proteins, particularly P-glycoprotein (P-gp, ABCB1). In this study, we have tested the anticancer and multidrug resistance (MDR) modulation activity of 15 selenocompounds. Out of the tested compounds, K3, K4, and K7 achieved the highest sensitization rate in ovarian carcinoma cells (HOC/ADR) that are resistant to the action of the Adriamycin. These compounds induced oxidation stress, inhibited P-gp transport activity and altered ABC gene expression. To verify the effect of compounds, 3D cell models were used to better mimic in vivo conditions. K4 and K7 triggered the most significant ROS release. All selected selenoesters inhibited P-gp efflux in a dose-dependent manner while simultaneously altering the expression of the ABC genes, especially P-gp in paclitaxel-resistant breast carcinoma cells (MCF-7/PAX). K4, and K7 demonstrated sensitization potential in resistant ovarian spheroids. Additionally, all selected selenoesters achieved a high cytotoxic effect in 3D breast and ovarian models, which was comparable to that in 2D cultures. K7 was the only non-competitive P-gp inhibitor, and therefore appears to have considerable potential for the treatment of drug-resistant cancer.

Intracellular Self-Assembly of Peptides to Induce Apoptosis against Drug-Resistant Melanoma.

Biosynthesis has been a diverse toolbox to develop bioactive molecules and materials, especially for fabricating modified peptides and their assemblies induced by enzymes. Although desired chemical structures and nanoarchitectures have been achieved, the subsequent interferences of peptide assemblies with organelles and the cellular pathways still remain unsolved important challenges. Herein, we developed a new tripeptide, phenylalanine-phenylalanine-tyrosine (Phe-Phe-Tyr, or FFY), which can be intracellularly oxidized and in situ self-assemble into nanoparticles with excellent interference capability with microtubules and ultimately reverse the drug resistance of melanoma. With the catalysis of tyrosinase, FFY was first oxidized to a melanin-like FFY dimer (mFFY) with a diquinone structure for further self-assembling into mFFY assemblies, which could inhibit the self-polymerization of tubulin to induce severe G2/M arrest (13.9% higher than control). Afterward, mitochondrial dysfunction was also induced for overproduction of cleaved caspase 3 (3.1 times higher than control) and cleaved PARP (6.3 times higher), achieving a high level of resistant reversing without chemotherapeutic drugs. In vivo studies showed that the resistant melanoma tumor volumes were reduced by 87.4% compared to control groups after FFY treatment by peritumoral injections. Overall, this tyrosinase-induced tripeptide assembly has been demonstrated with effective intrinsic apoptosis against drug-resistant melanoma, providing a new insight into utilizing biomolecules to interfere with organelles to activate certain apoptosis pathways for treatment of drug-resistant cancer.

A transistor-like pH-sensitive nanodetergent for selective cancer therapy.

Plasma membrane rupture is a promising strategy for drug-resistant cancer treatment, but its application is limited by the low tumour selectivity of membranolytic molecules. Here we report the design of 'proton transistor' nanodetergents that can convert the subtle pH perturbation signals of tumour tissues into sharp transition signals of membranolytic activity for selective cancer therapy. Our top-performing 'proton transistor' nanodetergent, P(C6-Bn20), can achieve a >32-fold change in cytotoxicity with a 0.1 pH input signal. At physiological pH, P(C6-Bn20) self-assembles into neutral nanoparticles with inactive membranolytic blocks shielded by poly(ethylene glycol) shells, exhibiting low toxicity. At tumour acidity, a sharp transition in its protonation state induces a morphological transformation and an activation of the membranolytic blocks, and the cation-π interaction facilitates the insertion of benzyl groups-containing hydrophobic domains into the cell membranes, resulting in potent membranolytic activity. P(C6-Bn20) is well tolerated in mice and shows high anti-tumour efficacy in various mouse tumour models.

A pH-responsive complex based on supramolecular organic framework for drug-resistant breast cancer therapy

Chemotherapy is one of the main ways to treat breast cancer clinically. However, the multidrug resistance to anti-tumor drugs limits their clinical use. To overcome these drawbacks, development of drug delivery systems (DDSs) has attracted more and more attention in cancer therapy. At present, the preparation and purification process are complicated for many reported DDSs, while clinic calls for new DDSs that are more convenient for preparation. Here, a new pH-responsive supramolecular organic framework drug delivery complex loading doxorubicin (DOX) is fabricated. Anti-tumor activity of the system in vitro was investigated by cell cytotoxicity, uptake assay, and cell apoptosis analysis. The anti-tumor activity in vivo was investigated by inspecting nude mice body weight, tumor volume, and weight, also a preliminary mechanism probe was conducted by HE and TUNEL staining. The DOX@SOF displayed high stability, good biocompatibility, and pH regulated drug release. At acid condition, the hydrazone bonds would be broken, which result in the dissociation of SOF, and then the drugs would be released from the system. Furthermore, DOX@SOF enhanced cellular internalization. Both in vitro and in vivo experiments reflected that DOX@SOF could enhance the anti-tumor activity of DOX for the MCF-7/ADR tumor cells and tumors. This study provides a highly efficient strategy to prepare stimulus-responsive supramolecular drug delivery complex for treatment of drug-resistant cancer, the results presented inspiring scientific interests in exploring new drug delivery strategy and reversing multi-drug resistance for clinical chemotherapy.

A pH-responsive complex based on supramolecular organic framework for drug-resistant breast cancer therapy

Chemotherapy is one of the main ways to treat breast cancer clinically. However, the multidrug resistance to anti-tumor drugs limits their clinical use. To overcome these drawbacks, the development of drug delivery systems (DDSs) has attracted more and more attention in cancer therapy. At present, the preparation and purification process are complicated for many reported DDSs, while the clinic calls for new DDSs that are more convenient for preparation. Here a new pH-responsive supramolecular organic framework drug delivery complex loading doxorubicin (DOX) is fabricated. Anti-tumor activity of the system in vitro was investigated by cell cytotoxicity, uptake assay, and cell apoptosis analysis. The anti-tumor activity in vivo was investigated by inspecting nude mice body weight, tumor volume and weight, also a preliminary mechanism probe was conducted by HE and TUNEL staining. The DOX@SOF displayed high stability, good biocompatibility and pH-regulated drug release. At acid condition, the hydrazone bonds would be broken, which result in the dissociation of SOF, and then the drugs would be released from the system. Furthermore, DOX@SOF enhanced cellular internalization. Both in vitro and in vivo experiments reflected that DOX@SOF could enhance the anti-tumor activity of DOX. for the MCF-7/ADR tumor cells and tumors. This study provides a highly efficient strategy to prepare a stimulus-responsive supramolecular drug delivery complex for the treatment of drug-resistant cancer, the results presented inspiring scientific interests in exploring new drug delivery strategies and reversing multi-drug resistance for clinical chemotherapy.

Synergistic effect of folate-conjugated polymers and 5-fluorouracil in the treatment of colon cancer

BackgroundIn recent years, targeted drug delivery strategies have received special attention from the scientific world due to advantages such as more effective therapy and reduction of side effects. The principle of operation is delayed excretion from the bloodstream of the drug delivery system compared to the drug itself, as well as facilitated penetration into diseased cells thanks to the use of ligands recognized by appropriate receptors. Particularly interesting drug carriers are amphiphilic copolymers that form nano-sized micelles with a drug, which can release the drug at a specific place in the body under the influence of appropriate stimuli.ResultsWe describe the synthesis of the diblock polymer, poly(2-hydroxyethyl acrylate)-b-poly(N-vinylcaprolactam) using RAFT/MADIX (Reversible Addition-Fragmentation chain Transfer/MAcromolecular Design by Interchange of Xanthate) controlled polymerization affording polymers with good dispersity according to SEC (Size-Exclusion Chromatography). Some post-modifications of the polymer with folic acid were then performed as evidenced by NMR (Nuclear Magnetic Resonance), UV–Vis (UltraViolet–Visible) and FT-IR (Fourier-Transform Infrared) spectroscopy, and TGA (ThermoGravimetric Analysis). The formation of stable micellar systems from polymers with and without the drug, 5-fluorouracil, was confirmed by DLS (Dynamic Light Scattering) and zeta potential measurements, and TEM (Transmission Eelectron Microscopy) imaging. Finally, the cloud point of the polymers was investigated, which turned out to be close to the temperature of the human body. Most importantly, these micellar systems have been explored as a drug delivery system against colon cancer, showing increased cytotoxicity compared to the drug alone. This effect was achieved due to the easier cellular uptake by the interaction of folic acid and its receptors on the surface of cancer cells.ConclusionsThe presented results constitute a solid foundation for the implementation of a nano-sized drug delivery system containing folic acid for practical use in the treatment of drug-resistant cancer, as well as more effective therapy with fewer side effects.Graphical

Yolk-Shell-Type Gold Nanoaggregates for Chemo- and Photothermal Combination Therapy for Drug-Resistant Cancers.

Epithelial ovarian cancer is a gynecological cancer with the highest mortality rate, and it exhibits resistance to conventional drugs. Gold nanospheres have gained increasing attention over the years as photothermal therapeutic nanoparticles, owing to their excellent biocompatibility, chemical stability, and ease of synthesis; however, their practical application has been hampered by their low colloidal stability and photothermal effects. In the present study, we developed a yolk-shell-structured silica nanocapsule encapsulating aggregated gold nanospheres (aAuYSs) and examined the photothermal effects of aAuYSs on cell death in drug-resistant ovarian cancers both in vitro and in vivo. The aAuYSs were synthesized using stepwise silica seed synthesis, surface amino functionalization, gold nanosphere decoration, mesoporous organosilica coating, and selective etching of the silica template. Gold nanospheres were agglomerated in the confined silica interior of aAuYSs, resulting in the red-shifting of absorbance and enhancement of the photothermal effect under 808 nm laser irradiation. The efficiency of photothermal therapy was first evaluated by inducing aAuYS-mediated cell death in A2780 ovarian cancer cells, which were cultured in a two-dimensional culture and a three-dimensional spheroid culture. We observed that photothermal therapy using aAuYSs together with doxorubicin treatment synergistically induced the cell death of doxorubicin-resistant A2780 cancer cells in vitro. Furthermore, this type of combinatorial treatment with photothermal therapy and doxorubicin synergistically inhibited the in vivo tumor growth of doxorubicin-resistant A2780 cancer cells in a xenograft transplantation model. These results suggest that photothermal therapy using aAuYSs is highly effective in the treatment of drug-resistant cancers.

Synthesis, computational docking and biological evaluation of celastrol derivatives as dual inhibitors of SERCA and P-glycoprotein in cancer therapy.

A series of eleven celastrol derivatives was designed, synthesized, and evaluated for their invitro cytotoxic activities against six human cancer cell lines (A549, HepG2, HepAD38, PC3, DLD-1 Bax-Bak WT and DKO) and three human normal cells (LO2, BEAS-2B, CCD19Lu). To our knowledge, six derivatives were the first example of dipeptide celastrol derivatives. Among them, compound 3 was the most promising derivative, as it exhibited a remarkable anti-proliferative activity and improved selectivity in liver cancer HepAD38 versus human normal hepatocytes, LO2. Compound 6 showed higher selectivity in liver cancer cells against human normal lung fibroblasts, CCD19Lu cell line. The Ca2+ mobilizations of 3 and 6 were also evaluated in the presence and absence of thapsigargin to demonstrate their inhibitory effects on SERCA. Derivatives 3 and 6 were found to induce apoptosis on LO2, HepG2 and HepAD38cells. The potential docking poses of all synthesized celastrol dipeptides and other known inhibitors were proposed by molecular docking. Finally, 3 inhibited P-gp-mediated drug efflux with greater efficiency than inhibitor verapamil in A549 lung cancer cells. Therefore, celastrol-dipeptide derivatives are potent drug candidates for the treatment of drug-resistant cancer.

Epigenetic Alterations and Mechanisms That Drive Resistance to Targeted Cancer Therapies.

Cancer is a complex disease and cancer cells typically harbor multiple genetic and epigenetic alterations. Large-scale sequencing of patient-derived cancer samples has identified several druggable driver oncogenes. Many of these oncogenes can be pharmacologically targeted to provide effective therapies for breast cancer, leukemia, lung cancer, melanoma, lymphoma, and other cancer types. Initial responses to these agents can be robust in many cancer types and some patients with cancer experience sustained tumor inhibition. However, resistance to these targeted therapeutics frequently emerges, either from intrinsic or acquired mechanisms, posing a major clinical hurdle for effective treatment. Several resistance mechanisms, both cell autonomous and cell nonautonomous, have been identified in different cancer types. Here we describe how alterations of the transcriptome, transcription factors, DNA, and chromatin regulatory proteins confer resistance to targeted therapeutic agents. We also elaborate on how these studies have identified underlying epigenetic factors that drive drug resistance and oncogenic pathways, with direct implications for the prevention and treatment of drug-resistant cancer.

The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future.

Simple SummaryDespite decades of extensive study into targeting cell death in breast cancer, including apoptosis, the clinical treatment remains challenging due to its high probability of recurrence. As an emerging form of cell death, ferroptosis features suppression of drug resistance and augmentation of antitumor immunity. The advances in the development of clinical drugs targeting ferroptosis provide growing silver linings for breast cancer treatment. Research into biomarkers to precisely trace ferroptosis in patients with cancer, and the development and subsequent application of novel ferroptosis-based therapies will be of critical importance in the next few years.Breast cancer (BC) is the most common malignancy among women worldwide. The discovery of regulated cell death processes has enabled advances in the treatment of BC. In the past decade, ferroptosis, a new form of iron-dependent regulated cell death caused by excessive lipid peroxidation has been implicated in the development and therapeutic responses of BC. Intriguingly, the induction of ferroptosis acts to suppress conventional therapy-resistant cells, and to potentiate the effects of immunotherapy. As such, pharmacological or genetic modulation targeting ferroptosis holds great potential for the treatment of drug-resistant cancers. In this review, we present a critical analysis of the current understanding of the molecular mechanisms and regulatory networks involved in ferroptosis, the potential physiological functions of ferroptosis in tumor suppression, its potential in therapeutic targeting, and explore recent advances in the development of therapeutic strategies for BC.

Ferroptosis: mechanisms, biology and role in disease.

The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.

A tumor-activatable peptide supramolecular nanoplatform for the delivery of dual-gene targeted siRNAs for drug-resistant cancer treatment.

Combinatorial short interference RNA (siRNA) technology for the silencing of multiple genes is expected to provide an effective therapeutic approach for cancer with complex genetic mutation and dysregulation. Herein we present a tumor-activatable supramolecular nanoplatform for the delivery of siRNAs to target telomerase and telomeres for paclitaxel-resistant non-small-cell lung cancer (A549/PTX) treatment. Two different sequences of siRNA are incorporated in a single nanoparticle, which is obtained by self-assembly from a peptide dendrimer. The siRNA stability is improved by the nanoparticle in the presence of serum compared to free siRNA, and these siRNAs are protected from RNA enzyme degradation. In the tumor extracellular acid environment, the PEG corona of the nanoparticle is removed to promote the internalization of siRNAs into tumor cells. The disulfide linkages between the nanoparticle and siRNAs are cleared in the reductive environment of the tumor cells, and the siRNAs are released in the cytoplasm. In vitro experiments show that the gene expression of hTERT and TRF2 at the mRNA and protein levels of A549/PTX tumor cells is down-regulated, which results in cooperative restraining proliferation and invasion of A549/PTX tumor cells. For the tumor cell-targeting function of the MUC1 aptamer and the EPR effect, sufficient tumor accumulation of nanoparticles was observed. Meanwhile, a shift of negative surface charge of nanoparticles to positive charge in the tumor extracellular microenvironment enhances deep penetration of siRNA-incorporating nanoparticles into tumor tissues. In vivo animal studies support that successful down-regulation of hTERT and TRF2 gene expression achieves effective inhibition of the growth and neovascularization of drug-resistant tumor cells. This work has provided a new avenue for drug-resistant cancer treatment by designing and synthesizing a tumor-activatable nanoplatform to achieve the delivery of dual-gene targeted combinatorial siRNAs.