Therapeutic Strategy For Cancer Therapy Research Articles

Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA+ B cells

BackgroundDysregulation of immune surveillance is tightly linked to the development of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC); however, its underlying mechanisms remain unclear. Herein, we aimed to determine the role of interleukin-21 receptor (IL-21R) in MASH-driven HCC.MethodsThe clinical significance of IL-21R was assessed in human HCC specimens using immunohistochemistry staining. Furthermore, the expression of IL-21R in mice was assessed in the STAM model. Thereafter, two different MASH-driven HCC mouse models were applied between IL-21R-deficient mice and wild type controls to explore the role of IL-21R in MASH-driven HCC. To further elucidate the potential mechanisms by which IL-21R affected MASH-driven HCC, whole transcriptome sequencing, flow cytometry and adoptive lymphocyte transfer were performed. Finally, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescent staining, chromatin immunoprecipitation assay and western blotting were conducted to explore the mechanism by which IL-21R induced IgA+ B cells.ResultsHCC patients with high IL-21R expression exhibited poor relapse-free survival, advanced TNM stage and severe steatosis. Additionally, IL-21R was demonstrated to be upregulated in mouse liver tumors. Particularly, ablation of IL-21R impeded MASH-driven hepatocarcinogenesis with dramatically reduction of lipid accumulation. Moreover, cytotoxic CD8+ T lymphocyte activation was enhanced in the absence of IL-21R due to the reduction of immunosuppressive IgA+ B cells. Mechanistically, the IL-21R-STAT1-c-Jun/c-Fos regulatory axis was activated in MASH-driven HCC and thus promoted the transcription of Igha, resulting in the induction of IgA+ B cells.ConclusionsIL-21R plays a cancer-promoting role by inducing IgA+ B cells in MASH-driven hepatocarcinogenesis. Targeting IL-21R signaling represents a potential therapeutic strategy for cancer therapy.

Hijacking cysteine metabolism for reversing hydrogen sulfide production in enhanced ferroptosis therapy

Intracellular cysteine (Cys) is an essential element in glutathione (GSH) biosynthesis, which endows cancer cell resistance to various therapies. In this study, we design a Cys metabolism hijacking strategy for converting cytoprotective Cys into therapeutic hydrogen sulfide (H2S), thus achieving enhanced ferroptosis therapy. A therapeutic nanoagent is first synthesized via the co-assembly of L-buthionine-sulfoximine (BSO) and plasmid encoding fn1055 with metal–organic framework (MOF) Fenton catalyst. The encapsulated BSO blocks the Cys-GSH biosynthesis pathway while the Fn1055 protein expressed from plasmid catalyzes the conversion of intracellular Cys to H2S, accelerating Cys-H2S metabolism. Due to its triple functionalities of intracellular acidification, catalase inhibition and mitophagy promotion, H2S significantly accelerates the MOF-induced ferroptosis, which is rationalized by the fully shrunken mitochondria. The in vivo administration of nanoagent effectively suppresses xenograft tumor growth without appreciable side effect. Such Cys metabolism hijacking provides a proof of concept for remolding the Cys-GSH pathway as a promising therapeutic strategy in cancer therapy.

Antagonists of transient receptor potential-mucolipin 1: A new therapeutic strategy for cancer therapy

Antagonists of transient receptor potential-mucolipin 1: A new therapeutic strategy for cancer therapy

A NAD(P)H oxidase mimic for catalytic tumor therapy via a deacetylase SIRT7-mediated AKT/GSK3β pathway.

Nicotinamide adenine dinucleotide (NADH) and its phosphorylated form, NADPH, are essential cofactors that play critical roles in cell functions, influencing antioxidation, reductive biosynthesis, and cellular pathways involved in tumor cell apoptosis and tumorigenesis. However, the use of nanomaterials to consume NAD(P)H and thus bring an impact on signaling pathways in cancer treatment remains understudied. In this study, we employed a salt template method to synthesize a carbon-coated-cobalt composite (C@Co) nanozyme, which exhibited excellent NAD(P)H oxidase (NOX)-like activity and mimicked the reaction mechanism of natural NOX. The C@Co nanozyme efficiently consumed NAD(P)H within cancer cells, leading to increased production of reactive oxygen species (ROS) and a reduction in mitochondrial membrane potential. Meanwhile, the generation of the biologically active cofactor NAD(P)+ promoted the expression of the deacetylase SIRT7, which in turn inhibited the serine/threonine kinase AKT signaling pathway, ultimately promoting apoptosis. This work sheds light on the influence of nanozymes with NOX-like activity on cellular signaling pathways in tumor therapy and demonstrates their promising antitumor effects in a tumor xenograft mouse model. These findings contribute to a better understanding of NAD(P)H manipulation in cancer treatment and suggest the potential of nanozymes as a therapeutic strategy for cancer therapy.

Use of oxygen-loaded nanobubbles to improve tissue oxygenation: Bone-relevant mechanisms of action and effects on osteoclast differentiation

Gas-loaded nanobubbles have potential as a method of oxygen delivery to increase tumour oxygenation and therapeutically alleviate tumour hypoxia. However, the mechanism(s) whereby oxygen-loaded nanobubbles increase tumour oxygenation are unknown; with their calculated oxygen-carrying capacity being insufficient to explain this effect. Intra-tumoural hypoxia is a prime therapeutic target, at least partly due to hypoxia-dependent stimulation of the formation and function of bone-resorbing osteoclasts which establish metastatic cells in bone. This study aims to investigate potential mechanism(s) of oxygen delivery and in particular the possible use of oxygen-loaded nanobubbles in preventing bone metastasis via effects on osteoclasts. Lecithin-based nanobubbles preferentially interacted with phagocytic cells (monocytes, osteoclasts) via a combination of lipid transfer, clathrin-dependent endocytosis and phagocytosis. This interaction caused general suppression of osteoclast differentiation via inhibition of cell fusion. Additionally, repeat exposure to oxygen-loaded nanobubbles inhibited osteoclast formation to a greater extent than nitrogen-loaded nanobubbles. This gas-dependent effect was driven by differential effects on the fusion of mononuclear precursor cells to form pre-osteoclasts, partly due to elevated potentiation of RANKL-induced ROS by nitrogen-loaded nanobubbles. Our findings suggest that oxygen-loaded nanobubbles could represent a promising therapeutic strategy for cancer therapy; reducing osteoclast formation and therefore bone metastasis via preferential interaction with monocytes/macrophages within the tumour and bone microenvironment, in addition to known effects of directly improving tumour oxygenation.

Emerging Roles of Using Small Extracellular Vesicles as an Anti-Cancer Drug.

Small extracellular vesicles (sEVs) are emerging as a novel therapeutic strategy for cancer therapy. Tumor-cell-derived sEVs contain biomolecules that can be utilized for cancer diagnosis. sEVs can directly exert tumor-killing effects or modulate the tumor microenvironment, leading to anti-cancer effects. In this review, the application of sEVs as a diagnostic tool, drug delivery system, and active pharmaceutical ingredient for cancer therapy will be highlighted. The therapeutic efficacies of sEVs will be compared to conventional immune checkpoint inhibitors. Additionally, this review will provide strategies for sEV engineering to enhance the therapeutic efficacies of sEVs. As a bench-to-bedside application, we will discuss approaches to encourage good-manufacturing-practice-compliant industrial-scale manufacturing and purification of sEVs.

PDE10A Inactivation Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth.

Cyclic nucleotides play critical roles in cardiovascular biology and disease. PDE10A (phosphodiesterase 10A) is able to hydrolyze both cAMP and cGMP. PDE10A expression is induced in various human tumor cell lines, and PDE10A inhibition suppresses tumor cell growth. Chemotherapy drug such as doxorubicin (DOX) is widely used in chemotherapy. However, cardiotoxicity of DOX remains to be a serious clinical complication. In the current study, we aim to determine the role of PDE10A and the effect of PDE10A inhibition on cancer growth and cardiotoxicity induced by DOX. We used global PDE10A knockout (KO) mice and PDE10A inhibitor TP-10 to block PDE10A function. DOX-induced cardiotoxicity was evaluated in C57Bl/6J mice and nude mice with implanted ovarian cancer xenografts. Isolated adult mouse cardiomyocytes and a human ovarian cancer cell line were used for in vitro functional and mechanistic studies. We found that PDE10A deficiency or inhibition alleviated DOX-induced myocardial atrophy, apoptosis, and dysfunction in C57Bl/6J mice. RNA sequencing study revealed a number of PDE10A-regulated signaling pathways involved in DOX-induced cardiotoxicity. PDE10A inhibition increased the death, decreased the proliferation, and potentiated the effect of DOX on various human cancer cells. Importantly, in nude mice with implanted ovarian cancer xenografts, PDE10A inhibition attenuated tumor growth while protecting DOX-induced cardiotoxicity. In isolated cardiomyocytes, PDE10A contributed to DOX-induced cardiomyocyte death via increasing Top2β (topoisomerase 2β) expression, mitochondrial dysfunction, and DNA damage by antagonizing cGMP/PKG (protein kinase G) signaling. PDE10A contributed to cardiomyocyte atrophy via potentiating FoxO3 (forkhead box O3) signaling via both cAMP/PKA (protein kinase A)- and cGMP/PKG-dependent signaling. Taken together, our study elucidates a novel role for PDE10A in cardiotoxicity induced by DOX and cancer growth. Given that PDE10A has been already proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy in cancer therapy, with effects preventing DOX-induced cardiotoxicity and simultaneously antagonizing cancer growth.

Discovery of a Potent and Oral Available Complex I OXPHOS Inhibitor That Abrogates Tumor Growth and Circumvents MEKi Resistance.

Targeting oxidative phosphorylation (OXPHOS) has emerged as a promising therapeutic strategy for cancer therapy. Here, we discovered a 1H-1,2,3-triazole derivative HP661 as a highly potent and orally available OXPHOS inhibitor that effectively blocked the activity of mitochondrial complex I. HP661 specifically compromised the mitochondrial oxygen consumption of high-OXPHOS lung cancer cells but not that of low-OXPHOS lung cancer cells or normal cells in the low nanomolar range. Notably, mitogen-activated protein kinase kinase (MEK) inhibitor (trametinib)-resistant lung cancer cells with high levels of OXPHOS also showed marked sensitivity to HP661, as indicated by decreased clonogenic growth and increased cell apoptosis upon treatment. In a mouse model of high-OXPHOS lung cancer, HP661 treatment not only significantly suppressed tumor growth but also augmented the therapeutic efficacy of trametinib by impairing tumor mitochondrial respiration. In summary, we identified HP661 as a highly effective OXPHOS inhibitor to abrogate the growth of high OXPHOS-dependent tumors and conquer high OXPHOS-mediated drug resistance.

The key role of microRNA-766 in the cancer development.

Cancer is caused by defects in coding and non-coding RNAs. In addition, duplicated biological pathways diminish the efficacy of mono target cancer drugs. MicroRNAs (miRNAs) are short, endogenous, non-coding RNAs that regulate many target genes and play a crucial role in physiological processes such as cell division, differentiation, cell cycle, proliferation, and apoptosis, which are frequently disrupted in diseases such as cancer. MiR-766, one of the most adaptable and highly conserved microRNAs, is notably overexpressed in several diseases, including malignant tumors. Variations in miR-766 expression are linked to various pathological and physiological processes. Additionally, miR-766 promotes therapeutic resistance pathways in various types of tumors. Here, we present and discuss evidence implicating miR-766 in the development of cancer and treatment resistance. In addition, we discuss the potential applications of miR-766 as a therapeutic cancer target, diagnostic biomarker, and prognostic indicator. This may shed light on the development of novel therapeutic strategies for cancer therapy.

Efficient tumor synergistic chemoimmunotherapy by self-augmented ROS-responsive immunomodulatory polymeric nanodrug

Immunotherapy has emerged as a promising therapeutic strategy for cancer therapy. However, the therapeutic efficacy has been distracted due to poor immunogenicity and immunosuppressive tumor microenvironment. In this study, a self-augmented reactive oxygen species (ROS) responsive nanocarrier with immunogenic inducer paclitaxel (PTX) and indoleamine 2,3-dixoygenase 1 (IDO1) blocker 1-methyl-d, L-tryptophan (1-MT) co-entrapment was developed for tumor rejection. The carrier was composed of poly (ethylene glycol) (PEG) as hydrophilic segments, enzyme cleavable 1-MT ester and ROS-sensitive peroxalate conjugation as hydrophobic blocks. The copolymer could self-assemble into prodrug-based nanoparticles with PTX, realizing a positive feedback loop of ROS-accelerated PTX release and PTX induced ROS generation. Our nanoparticles presented efficient immunogenic cell death (ICD) which provoked antitumor immune responses with high effector T cells infiltration. Meanwhile immunosuppressive tumor microenvironment was simultaneously modulated with reduced regulatory T cells (Tregs) and M2-tumor associated macrophages (M2-TAMs) infiltration mediated by IDO inhibition. The combination of PTX and 1-MT achieved significant primary tumor regression and reduction of lung metastasis in 4T1 tumor bearing mice. Therefore, the above results demonstrated co-delivery of immunogenic inducer and IDO inhibitor using the ROS amplifying nanoplatform with potent potential for tumor chemoimmunotherapy.

Cancer-Specific Delivery of Proteolysis-Targeting Chimeras (PROTACs) and Their Application to Cancer Immunotherapy.

Proteolysis-targeting chimeras (PROTACs) are rapidly emerging as a potential therapeutic strategy for cancer therapy by inducing the degradation of tumor-overexpressing oncogenic proteins. They can specifically catalyze the degradation of target oncogenic proteins by recruiting E3 ligases and utilizing the ubiquitin-proteasome pathway. Since their mode of action is universal, irreversible, recyclable, long-lasting, and applicable to 'undruggable' proteins, PROTACs are gradually replacing the role of conventional small molecular inhibitors. Moreover, their application areas are being expanded to cancer immunotherapy as various types of oncogenic proteins that are involved in immunosuppressive tumor microenvironments. However, poor water solubility and low cell permeability considerably restrict the pharmacokinetic (PK) property, which necessitates the use of appropriate delivery systems for cancer immunotherapy. In this review, the general characteristics, developmental status, and PK of PROTACs are first briefly covered. Next, recent studies on the application of various types of passive or active targeting delivery systems for PROTACs are introduced, and their effects on the PK and tumor-targeting ability of PROTACs are described. Finally, recent drug delivery systems of PROTACs for cancer immunotherapy are summarized. The adoption of an adequate delivery system for PROTAC is expected to accelerate the clinical translation of PROTACs, as well as improve its efficacy for cancer therapy.

Discovery of Novel Lin28 Inhibitors to Suppress Cancer Cell Stemness.

Lin28 is a pluripotency factor that regulates cancer cell stem-like phenotypes to promote cancer development and therapy-resistant tumor progression. It acts through its cold shock domain and zinc knuckle domain (ZKD) to interact with the Let-7 pre-microRNA and block Let-7 biosynthesis. Chemical inhibition of Lin28 from interacting with Let-7 presents a therapeutic strategy for cancer therapy. Herein, we present the computer-aided development of small molecules by in silico screening 18 million compounds from the ZINC20 library, followed by the biological validation of 163 predicted compounds to confirm 15 new Lin28 inhibitors. We report three lead compounds, Ln7, Ln15, and Ln115, that target the ZKD of both Lin28A and Lin28B isoforms and block Lin28 from binding Let-7. They restore Let-7 expression and suppress tumor oncogenes such as SOX2 in cancer cells and show strong inhibitory effects on cancer cell stem-like phenotypes. However, minimal impacts of these compounds were observed on Lin28-negative cells, confirming the on-target effects of these compounds. We conclude from this study the discovery of several new Lin28 inhibitors as promising candidate compounds that warrant further drug development into potential anticancer therapies.

Analyzing Lymphoma Development and Progression Using HDACi in Mouse Models.

Besides the physiological role of histone deacetalylases in maintaining normal cellular integrity, the acetylation landscape is changed in cancer cells, which has been implicated as a potential target in cancer therapy. The overexpression of certain HDACs correlates with specific cancer types. Therefore, the development of specific HDAC inhibitors may extend the therapeutic strategy for cancer therapy. Here, we describe how to investigate the therapeutic potential of specific HDACi by treatment in a mouse model for B-cell lymphoma, exemplified by the HDAC6 inhibitor Marbostat-100.

Porphyrin‐Based Covalent Organic Framework for Imaging‐Guided Cancer Combinatorial Immuno‐Sonodynamic Therapy

AbstractThe rational design of tumor microenvironment (TME)‐activated nanomedicine is driving a new direction in tumor immunology. Furthermore, the novel therapeutic mode of ultrasound‐triggered sonodynamic therapy (SDT) has been proven to specifically activate the immune response. Herein, a well‐defined covalent organic framework (COF) with sonosensitive properties is synthesized through experimental and theoretical verification, followed by the efficient loading of the toll‐like receptor agonist (Poly(I:C)) and in situ growth of paramagnetic transitional metallic oxide of manganese bioxide (MnO2). The MnO2‐Poly(I:C)@COF shell can reverse the reductive TME by consuming glutathione (GSH) to release Mn2+, simultaneously generating marked magnetic resonance imaging signals for real‐time guidance. Importantly, the MnO2 acts as an enzyme‐like nano‐catalyst to promote TME‐overexpressed hydrogen peroxide (H2O2) and produce oxygen, facilitating SDT‐induced reactive oxygen species production, and inducing immunogenic cell death, thereby boosting immune engine and triggering abundant neoantigen exposure. With the powerful assistance of immunological agents Mn2+ and Poly(I:C), the triggered immune engine is amplified by refueling the engine (stepping on the accelerator) to reduce the immunosuppressive state. Overall, this study improves the synthesis of multifunctional COF and expands its application. The developed nano‐sonosensitizer system provides a paradigm to enhance SDT‐based high‐performance multifunctional sonosensitizers, and this SDT‐mediated strong tumor‐suppressive efficiency and activated immune effect represent a promising combinatorial therapeutic strategy for cancer therapy.

Inhibiting Cytoprotective Autophagy in Cancer Therapy: An Update on Pharmacological Small-Molecule Compounds.

Autophagy is a self-degradation process in which damaged proteins and organelles are engulfed into autophagosomes for digestion and eventually recycled for cellular metabolism to maintain intracellular homeostasis. Accumulating studies have reported that autophagy has the Janus role in cancer as a tumor suppressor or an oncogenic role to promote the growth of established tumors and developing drug resistance. Importantly, cytoprotective autophagy plays a prominent role in many types of human cancers, thus inhibiting autophagy, and has been regarded as a promising therapeutic strategy for cancer therapy. Here, we focus on summarizing small-molecule compounds inhibiting the autophagy process, as well as further discuss other dual-target small-molecule compounds, combination strategies, and other strategies to improve potential cancer therapy. Therefore, these findings will shed new light on exploiting more small-molecule compounds inhibiting cytoprotective autophagy as candidate drugs for fighting human cancers in the future.

Dual inhibition of glucose uptake and energy supply synergistically restrains the growth and metastasis of breast cancer

Metastatic breast cancer (MBC) is one of the most common and knotty diseases in female population which could place them in a life-threatening condition. For malignant proliferation and migration, cancer cells require a large amount of glucose and energy to meet the demand of rapid metabolism. Hence, efficiently diminishing the utilization of energy substances by cancer cells is emerging as validated therapeutic strategies for cancer therapy. Herein, a nanoplatform with dual-inhibition of glucose uptake and oxidative phosphorylation (OXPHOS) was designed, which consisted of albendazole (ABZ) and atovaquone (ATO) by simple carrier-free self-assembling. The introduction of ABZ could evidently decrease glucose uptake to reduce the main “energy fuel” of cancer cells. Meanwhile, as a blocker of OXPHOS, ATO would reduce adenosine triphosphate (ATP) production and ameliorate hypoxia microenvironment by suppressing mitochondrial respiratory chain. Under such dual inhibition of energy metabolism, AA NPs exerted synergistic energy exhaustion effect and outstanding hypoxia improvement function, efficiently inhibiting tumor growth and metastasis. This research not only illustrates the feasibility of energy metabolism therapy by co-inhibiting glucose uptake and OXPHOS, but also provides an ingenious tactic to diminish metastasis during MBC treatment

The functions of long noncoding RNAs on regulation of F-box proteins in tumorigenesis and progression.

Accumulated evidence has revealed that F-box protein, a subunit of SCF E3 ubiquitin ligase complexes, participates in carcinogenesis and tumor progression via targeting its substrates for ubiquitination and degradation. F-box proteins could be regulated by cellular signaling pathways and noncoding RNAs in tumorigenesis. Long noncoding RNA (lncRNA), one type of noncoding RNAs, has been identified to modulate the expression of F-box proteins and contribute to oncogenesis. In this review, we summarize the role and mechanisms of multiple lncRNAs in regulating F-box proteins in tumorigenesis, including lncRNAs SLC7A11-AS1, MT1JP, TUG1, FER1L4, TTN-AS1, CASC2, MALAT1, TINCR, PCGEM1, linc01436, linc00494, GATA6-AS1, and ODIR1. Moreover, we discuss that targeting these lncRNAs could be helpful for treating cancer via modulating F-box protein expression. We hope our review can stimulate the research on exploration of molecular insight into how F-box proteins are governed in carcinogenesis. Therefore, modulation of lncRNAs is a potential therapeutic strategy for cancer therapy via regulation of F-box proteins.

Cuproptosis-Associated lncRNA Establishes New Prognostic Profile and Predicts Immunotherapy Response in Clear Cell Renal Cell Carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) accounts for 80% of all kidney cancers and has a poor prognosis. Recent studies have shown that copper-dependent, regulated cell death differs from previously known death mechanisms (apoptosis, ferroptosis, and necroptosis) and is dependent on mitochondrial respiration (Tsvetkov et al., Science, 2022, 375 (6586), 1254–1261). Studies also suggested that targeting cuproptosis may be a novel therapeutic strategy for cancer therapy. In ccRCC, both cuproptosis and lncRNA were critical, but the mechanisms were not fully understood. The aim of our study was to construct a prognostic profile based on cuproptosis-associated lncRNAs to predict the prognosis of ccRCC and to study the immune profile of clear cell renal cell carcinoma (ccRCC). Methods: We downloaded the transcriptional profile and clinical information of ccRCC from The Cancer Genome Atlas (TCGA). Co-expression network analysis, Cox regression method, and least absolute shrinkage and selection operator (LASSO) method were used to identify cuproptosis-associated lncRNAs and to construct a risk prognostic model. In addition, the predictive performance of the model was validated and recognized by an integrated approach. We then also constructed a nomogram to predict the prognosis of ccRCC patients. Differences in biological function were investigated by GO, KEGG, and immunoassay. Immunotherapy response was measured using tumor mutational burden (TMB) and tumor immune dysfunction and rejection (TIDE) scores. Results: We constructed a panel of 10 cuproptosis-associated lncRNAs (HHLA3, H1-10-AS1, PICSAR, LINC02027, SNHG15, SNHG8, LINC00471, EIF1B-AS1, LINC02154, and MINCR) to construct a prognostic prediction model. The Kaplan–Meier and ROC curves showed that the feature had acceptable predictive validity in the TCGA training, test, and complete groups. The cuproptosis-associated lncRNA model had higher diagnostic efficiency compared to other clinical features. The analysis of Immune cell infiltration and ssGSEA further confirmed that predictive features were significantly associated with the immune status of ccRCC patients. Notably, the superimposed effect of patients in the high-risk group and high TMB resulted in shorter survival. In addition, the higher TIDE scores in the high-risk group suggested a poorer outcome for immune checkpoint blockade response in these patients. Conclusion: The ten cuproptosis-related risk profiles for lncRNA may help assess the prognosis and molecular profile of ccRCC patients and improve treatment options, which can be further applied in the clinic.

TP53 Co-Mutations in Advanced EGFR-Mutated Non-Small Cell Lung Cancer: Prognosis and Therapeutic Strategy for Cancer Therapy.

Lung cancer is the leading cause of cancer-related deaths worldwide. As the most prevalent molecular mutation subtypes in non-small cell lung cancer (NSCLC), EGFR-TKIs are currently a standard first-line therapy for targeting the mutated EGFR in advanced NSCLC patients. However, 20-30% of this subset of patients shows primary resistance to EGFR-TKIs. Patients with co-mutations of EGFR and several other genes have a poor response to EGFR-TKIs, whereas the prognostic and predictive significance of EGFR/TP53 co-mutation in NSCLC patients remains controversial. Meanwhile, little is known about how to choose an optimal therapeutic strategy for this subset of patients. Presently, no drugs targeting TP53 mutations are available on the market, and some p53 protein activators are in the early stage of clinical trials. A combination of EGFR-TKIs with antiangiogenic agents or chemotherapy or other agents might be a more appropriate strategy to tackle the problem. In this review, we describe the prognostic and predictive value of EGFR/TP53 co-mutation in NSCLC patients, investigate the mechanisms of this co-mutation affecting the response to EGFR-TKIs, and further explore optimal regimens effectively to prolong the survival time of the NSCLC patients harboring this co-mutation.

Regulation of Ferroptosis by Amino Acid Metabolism in Cancer.

Ferroptosis, a new form of programmed necrosis characterized by iron-dependent lethal accumulation of lipid hydroperoxides, is associated with many human diseases. Targeting amino acid (AA) availability can selectively suppress tumor growth and has been a promising therapeutic strategy for cancer therapy. Compelling studies have indicated that AA metabolism is also involved in ferroptosis, closely regulating its initiation and execution. This manuscript systematically summarizes the latest advances of AA metabolism in regulating ferroptosis and discusses the potential combination of therapeutic strategies that simultaneously target AA metabolism and ferroptosis in cancer to eliminate tumors or limit their invasiveness.