Leveraging Cancer Phenotypic Plasticity for Novel Treatment Strategies.

Cancer cells, like all other organisms, are adept at switching their phenotype to adjust to the changes in their environment. Thus, phenotypic plasticity is a quantitative trait that confers a fitness advantage to the cancer cell by altering its phenotype to suit environmental circumstances. Until recently, new traits, especially in cancer, were thought to arise due to genetic factors; however, it is now amply evident that such traits could also emerge non-genetically due to phenotypic plasticity. Furthermore, phenotypic plasticity of cancer cells contributes to phenotypic heterogeneity in the population, which is a major impediment in treating the disease. Finally, plasticity also impacts the group behavior of cancer cells, since competition and cooperation among multiple clonal groups within the population and the interactions they have with the tumor microenvironment also contribute to the evolution of drug resistance. Thus, understanding the mechanisms that cancer cells exploit to tailor their phenotypes at a systems level can aid the development of novel cancer therapeutics and treatment strategies. Here, we present our perspective on a team medicine-based approach to gain a deeper understanding of the phenomenon to develop new therapeutic strategies.

Emerging biomarkers and molecular targets for precision medicine in cervical cancer.

Cervical cancer remains a significant global health burden, necessitating innovative approaches for improved diagnostics and personalized treatment strategies. Precision medicine has emerged as a promising paradigm, leveraging biomarkers and molecular targets to tailor therapy to individual patients. This review explores the landscape of emerging biomarkers and molecular targets in cervical cancer, highlighting their potential implications for precision medicine. By integrating these biomarkers into comprehensive diagnostic algorithms, clinicians can identify high-risk patients at an earlier stage, enabling timely intervention and improved patient outcomes. Furthermore, the identification of specific molecular targets has paved the way for the development of targeted therapies aimed at disrupting key pathways implicated in cervical carcinogenesis. In conclusion, the evolving landscape of biomarkers and molecular targets presents exciting opportunities for advancing precision medicine in cervical cancer. By harnessing these insights, clinicians can optimize treatment selection, enhance patient outcomes, and ultimately transform the management of this devastating disease.

A Nexus between Genetic and Non-Genetic Mechanisms Guides KRAS Inhibitor Resistance in Lung Cancer.

Several studies in the last few years have determined that, in contrast to the prevailing dogma that drug resistance is simply due to Darwinian evolution-the selection of mutant clones in response to drug treatment-non-genetic changes can also lead to drug resistance whereby tolerant, reversible phenotypes are eventually relinquished by resistant, irreversible phenotypes. Here, using KRAS as a paradigm, we illustrate how this nexus between genetic and non-genetic mechanisms enables cancer cells to evade the harmful effects of drug treatment. We discuss how the conformational dynamics of the KRAS molecule, that includes intrinsically disordered regions, is influenced by the binding of the targeted therapies contributing to conformational noise and how this noise impacts the interaction of KRAS with partner proteins to rewire the protein interaction network. Thus, in response to drug treatment, reversible drug-tolerant phenotypes emerge via non-genetic mechanisms that eventually enable the emergence of irreversible resistant clones via genetic mutations. Furthermore, we also discuss the recent data demonstrating how combination therapy can help alleviate KRAS drug resistance in lung cancer, and how new treatment strategies based on evolutionary principles may help minimize or even preclude the emergence of drug resistance.

Artificial intelligence and allied subsets in early detection and preclusion of gynecological cancers.

Gynecological cancers including breast, cervical, ovarian, uterine, and vaginal, pose the greatest threat to world health, with early identification being crucial to patient outcomes and survival rates. The application of machine learning (ML) and artificial intelligence (AI) approaches to the study of gynecological cancer has shown potential to revolutionize cancer detection and diagnosis. The current review outlines the significant advancements, obstacles, and prospects brought about by AI and ML technologies in the timely identification and accurate diagnosis of different types of gynecological cancers. The AI-powered technologies can use genomic data to discover genetic alterations and biomarkers linked to a particular form of gynecologic cancer, assisting in the creation of targeted treatments. Furthermore, it has been shown that the potential benefits of AI and ML technologies in gynecologic tumors can greatly increase the accuracy and efficacy of cancer diagnosis, reduce diagnostic delays, and possibly eliminate the need for needless invasive operations. In conclusion, the review focused on the integrative part of AI and ML based tools and techniques in the early detection and exclusion of various cancer types; together with a collaborative coordination between research clinicians, data scientists, and regulatory authorities, which is suggested to realize the full potential of AI and ML in gynecologic cancer care.

Acquired resistance to KRAS G12C small-molecule inhibitors via genetic/nongenetic mechanisms in lung cancer.

Inherent or acquired resistance to sotorasib poses a substantialt challenge for NSCLC treatment. Here, we demonstrate that acquired resistance to sotorasib in isogenic cells correlated with increased expression of integrin ß4 (ITGB4), a component of the focal adhesion complex. Silencing ITGB4 in tolerant cells improved sotorasib sensitivity, while overexpressing ITGB4 enhanced tolerance to sotorasib by supporting AKT-mTOR bypass signaling. Chronic treatment with sotorasib induced WNT expression and activated the WNT/ß-catenin signaling pathway. Thus, silencing both ITGB4 and ß-catenin significantly improved sotorasib sensitivity in tolerant, acquired, and inherently resistant cells. In addition, the proteasome inhibitor carfilzomib (CFZ) exhibited synergism with sotorasib by down-regulating ITGB4 and ß-catenin expression. Furthermore, adagrasib phenocopies the combination effect of sotorasib and CFZ by suppressing KRAS activity and inhibiting cell cycle progression in inherently resistant cells. Overall, our findings unveil previously unrecognized nongenetic mechanisms underlying resistance to sotorasib and propose a promising treatment strategy to overcome resistance.

Regression of ovarian cancer xenografts by depleting or inhibiting RLIP.

Ovarian cancer (OC) is the most prevalent and deadly cancer of the female reproductive system. Women will continue to be impacted by OC-related morbidity and mortality. Despite the fact that chemotherapy with cisplatin is the main component as the first-line anticancer treatment for OC, chemoresistance and unfavorable side effects are important obstacles to effective treatment. Targets for effective cancer therapy are required for cancer cells but not for non-malignant cells because they are expressed differently in cancer cells compared to normal cells. Targets for cancer therapy should preferably be components that already exist in biochemical and signalling frameworks and that significantly contribute to the development of cancer or regulate the response to therapy. RLIP is an important mercapturic acid pathway transporter that is crucial for survival and therapy resistance in cancers, therefore, we examined the role of RLIP in regulating essential signalling proteins involved in relaying the inputs from upstream survival pathways and mechanisms contributing to chemo-radiotherapy resistance in OC. The findings of our research offer insight into a novel anticancer effect of RLIP depletion/inhibition on OC and might open up new therapeutic avenues for OC therapy.

Targeting ITGB4/SOX2-driven lung cancer stem cells using proteasome inhibitors.

This study investigates the role of integrin ß4 (ITGB4) and stemness-associated factor SOX2 in platinum resistance in lung squamous cell carcinoma (LUSC). The expression of SOX2 and ITGB4 is found to be high in all LUSC subtypes, but the impact of ITGB4 expression on overall patient survival varies by subtype. Cancer stem cells (CSCs) isolated from LUSC patients were found to be resistant to cisplatin, but knocking down ITGB4 or SOX2 sensitized them to cisplatin. Carfilzomib (CFZ) synergized with cisplatin and suppressed CSC growth by inhibiting ITGB4 and SOX2 expression. Additionally, CFZ was found to inhibit SOX2 expression epigenetically by inhibiting histone acetylation at the SOX2 promoter site. CFZ also suppressed the growth of SOX2-dependent small cell lung cancer cells in vitro and in vivo. The study highlights the unique function of CFZ as a transcriptional suppressor of SOX2, independent of its proteasome inhibitory function.

Recent Advancement in Breast Cancer Research: Insights from Model Organisms-Mouse Models to Zebrafish.

Animal models have been utilized for decades to investigate the causes of human diseases and provide platforms for testing novel therapies. Indeed, breakthrough advances in genetically engineered mouse (GEM) models and xenograft transplantation technologies have dramatically benefited in elucidating the mechanisms underlying the pathogenesis of multiple diseases, including cancer. The currently available GEM models have been employed to assess specific genetic changes that underlay many features of carcinogenesis, including variations in tumor cell proliferation, apoptosis, invasion, metastasis, angiogenesis, and drug resistance. In addition, mice models render it easier to locate tumor biomarkers for the recognition, prognosis, and surveillance of cancer progression and recurrence. Furthermore, the patient-derived xenograft (PDX) model, which involves the direct surgical transfer of fresh human tumor samples to immunodeficient mice, has contributed significantly to advancing the field of drug discovery and therapeutics. Here, we provide a synopsis of mouse and zebrafish models used in cancer research as well as an interdisciplinary 'Team Medicine' approach that has not only accelerated our understanding of varied aspects of carcinogenesis but has also been instrumental in developing novel therapeutic strategies.

The innate effects of plant secondary metabolites in preclusion of gynecologic cancers: Inflammatory response and therapeutic action.

Gynecologic cancers can make up the bulk of cancers in both humans and animals. The stage of diagnosis and the type of tumor, its origin, and its spread are a few of the factors that influence how effectively a treatment modality works. Currently, radiotherapy, chemotherapy, and surgery are the major treatment options recommended for the eradication of malignancies. The use of several anti-carcinogenic drugs increases the chance of harmful side effects, and patients might not react to the treatments as expected. The significance of the relationship between inflammation and cancer has been underscored by recent research. As a result, it has been shown that a variety of phytochemicals with beneficial bioactive effects on inflammatory pathways have the potential to act as anti-carcinogenic medications for the treatment of gynecologic cancer. The current paper reviews the significance of inflammatory pathways in gynecologic malignancies and discusses the role of plants-derived secondary metabolites that are useful in the treatment of cancer.

Prognostic significance of natural products against multidrug tumor resistance.

Cancer is a pervasive, constantly evolving, and significant public health concern. The number of new cancer cases has risen dramatically in the last decades, making it one of the top causes of poor health and mortality worldwide. Although various treatment strategies, including surgery, radiation, and pharmaceutical therapies, have evolved into more sophisticated, precise methods, there is not much improvement in the cancer-related death toll. Consequently, natural product-based therapeutic discoveries have recently been considered an alternative approach. According to an estimate, one-third of the top twenty medications in today's market have a natural plant-product-based origin. Accordingly, primary prevention is an essential component of worldwide cancer control. This review provides an overview of the mechanisms of action of bioactive ingredients in natural dietary products that may contribute to the prevention and management of multiple malignancies.

A Systems Biology Approach for Addressing Cisplatin Resistance in Non-Small Cell Lung Cancer.

Translational research in medicine, defined as the transfer of knowledge and discovery from the basic sciences to the clinic, is typically achieved through interactions between members across scientific disciplines to overcome the traditional silos within the community. Thus, translational medicine underscores 'Team Medicine', the partnership between basic science researchers and clinicians focused on addressing a specific goal in medicine. Here, we highlight this concept from a City of Hope perspective. Using cisplatin resistance in non-small cell lung cancer (NSCLC) as a paradigm, we describe how basic research scientists, clinical research scientists, and medical oncologists, in true 'Team Science' spirit, addressed cisplatin resistance in NSCLC and identified a previously approved compound that is able to alleviate cisplatin resistance in NSCLC. Furthermore, we discuss how a 'Team Medicine' approach can help to elucidate the mechanisms of innate and acquired resistance in NSCLC and develop alternative strategies to overcome drug resistance.

Addressing Drug Resistance in Cancer: A Team Medicine Approach.

Drug resistance remains one of the major impediments to treating cancer. Although many patients respond well initially, resistance to therapy typically ensues. Several confounding factors appear to contribute to this challenge. Here, we first discuss some of the challenges associated with drug resistance. We then discuss how a 'Team Medicine' approach, involving an interdisciplinary team of basic scientists working together with clinicians, has uncovered new therapeutic strategies. These strategies, referred to as intermittent or 'adaptive' therapy, which are based on eco-evolutionary principles, have met with remarkable success in potentially precluding or delaying the emergence of drug resistance in several cancers. Incorporating such treatment strategies into clinical protocols could potentially enhance the precision of delivering personalized medicine to patients. Furthermore, reaching out to patients in the network of hospitals affiliated with leading academic centers could help them benefit from such innovative treatment options. Finally, lowering the dose of the drug and its frequency (because of intermittent rather than continuous therapy) can also have a significant impact on lowering the toxicity and undesirable side effects of the drugs while lowering the financial burden carried by the patient and insurance providers.

RLIP: A necessary transporter protein for translating oxidative stress into pro-obesity and pro-carcinogenic signaling.

Previously, we showed that knockout mice homozygous for deficiency of the mercapturic acid pathway (MAP) transporter protein, RLIP (RLIP-/-), are resistant to chemical carcinogenesis, inflammation, and metabolic syndrome (MetS). We also found that RLIP-/- mice are highly resistant to obesity caused by a high-fat diet (HFD). Interestingly, these studies showed that kinase, cytokine, and adipokine signaling that are characteristics of obesity were blocked despite the presence of increased oxidative stress in RLIP-/- mice. The deficiencies in obesity-inducing kinase, cytokine, and adipokine signaling were attributable to a lack of clathrin-dependent endocytosis (CDE), a process that is severely deficient in RLIP-/- mice. Because CDE is also necessary for carcinogenic signaling through EGF, WNT, TGFß and other cancer-specific peptide hormones, and because RLIP-/- mice are cancer-resistant, we reasoned that depletion of RLIP by an antisense approach should cause cancer regression in human cancer xenografts. This prediction has been confirmed in studies of xenografts from lung, kidney, prostate, breast, and pancreatic cancers and melanoma. Because these results suggested an essential role for RLIP in carcinogenesis, and because our studies have also revealed a direct interaction between p53 and RLIP, we reasoned that if RLIP played a central role in carcinogenesis, that development of lymphoma in p53-/- mice, which normally occurs by the time these mice are 6 months old, could be delayed or prevented by depleting RLIP. Recent studies described herein have confirmed this hypothesis, showing complete suppression of lymphomagenesis in p53-/- mice treated with anti-RLIP antisense until the age of 8 months. All control mice developed lymphoma in the thymus or testis as expected. These findings lead to a novel paradigm predicting that under conditions of increased oxidative stress, the consequent increased flux of metabolites in the MAP causes a proportional increase in the rate of CDE. Because CDE inhibits insulin and TNF signaling but promotes EGF, TGFß, and Wnt signaling, our model predicts that chronic stress-induced increases in RLIP (and consequently CDE) will induce insulin-resistance and enhance predisposition to cancer. Alternatively, generalized depletion of RLIP would antagonize the growth of malignant cells, and concomitantly exert therapeutic insulin-sensitizing effects. Therefore, this review focuses on how targeted depletion or inhibition of RLIP could provide a novel target for treating both obesity and cancer.

Chemokines and NSCLC: Emerging role in prognosis, heterogeneity, and therapeutics.

Lung cancer persists to contribute to one-quarter of cancer-associated deaths. Among the different histologies, non-small cell lung cancer (NSCLC) alone accounts for 85% of the cases. The development of therapies involving immune checkpoint inhibitors and angiogenesis inhibitors has increased patients' survival probability and reduced mortality rates. Developing targeted therapies against essential genetic alterations also translates to better treatment strategies. But the benefits still seem farfetched due to the development of drug resistance and refractory tumors. In this review, we have highlighted the interplay of different tumor microenvironment components, essentially discussing the chemokine families (CC, CXC, C, and CX3C) that regulate the tumor biology in NSCLC and promote tumor growth, metastasis, and associated heterogeneity. The development of therapeutics and prognostic markers is a complex and multipronged approach. However, some essential chemokines can act as critical players for being considered potential prognostic markers and therapeutic targets.

Correction: 2'-Hydroxyflavanone effectively targets RLIP76-mediated drug transport and regulates critical signaling networks in breast cancer.

[This corrects the article DOI: 10.18632/oncotarget.24720.].

Anticancer Activity of Ω-6 Fatty Acids through Increased 4-HNE in Breast Cancer Cells.

Her2-amplified breast cancers resistant to available Her2-targeted therapeutics continue to be a challenge in breast cancer therapy. Dox is the mainstay of chemotherapy of all types of breast cancer, but its usefulness is limited by cumulative cardiotoxicity. Because oxidative stress caused by dox generates the pro-apoptotic Ω-6 PUFA metabolite 4-hydroxynonenal (4-HNE), we surmised that Ω-6 PUFAs would increase the effectiveness of dox chemotherapy. Since the mercapturic acid pathway enzyme RALBP1 (also known as RLIP76 or Rlip) that limits cellular accumulation of 4-HNE also mediates dox resistance, the combination of Ω-6 PUFAs and Rlip depletion could synergistically improve the efficacy of dox. Thus, we studied the effects of the Ω-6 PUFA arachidonic acid (AA) and Rlip knockdown on the antineoplastic activity of dox towards Her2-amplified breast cancer cell lines SK-BR-3, which is sensitive to Her2 inhibitors, and AU565, which is resistant. AA increased lipid peroxidation, 4-HNE generation, apoptosis, cellular dox concentration and dox cytotoxicity in both cell lines while sparing cultured immortalized cardiomyocyte cells. The known functions of Rlip including clathrin-dependent endocytosis and dox efflux were inhibited by AA. Our results support a model in which 4-HNE generated by AA overwhelms the capacity of Rlip to defend against apoptosis caused by dox or 4-HNE. We propose that Ω-6 PUFA supplementation could improve the efficacy of dox or Rlip inhibitors for treating Her2-amplified breast cancer.

Haploinsufficiency Interactions between RALBP1 and p53 in ERBB2 and PyVT Models of Mouse Mammary Carcinogenesis.

We recently reported that loss of one or both alleles of Ralbp1, which encodes the stress-protective protein RLIP76 (Rlip), exerts a strong dominant negative effect on both the inherent cancer susceptibility and the chemically inducible cancer susceptibility of mice lacking one or both alleles of the tumor suppressor p53. In this paper, we examined whether congenital Rlip deficiency could prevent genetically-driven breast cancer in two transgenic mouse models: the MMTV-PyVT model, which expresses the polyomavirus middle T antigen (PyVT) under control of the mouse mammary tumor virus promoter (MMTV) and the MMTV-Erbb2 model which expresses MMTV-driven erythroblastic leukemia viral oncogene homolog 2 (Erbb2, HER2/Neu) and frequently acquires p53 mutations. We found that loss of either one or two Rlip alleles had a suppressive effect on carcinogenesis in Erbb2 over-expressing mice. Interestingly, Rlip deficiency did not affect tumor growth but significantly reduced the lung metastatic burden of breast cancer in the viral PyVT model, which does not depend on either Ras or loss of p53. Furthermore, spontaneous tumors of MMTV-PyVT/Rlip+/+ mice showed no regression following Rlip knockdown. Finally, mice lacking one or both Rlip alleles differentially expressed markers for apoptotic signaling, proliferation, angiogenesis, and cell cycling in PyVT and Erbb2 breast tumors. Our results support the efficacy of Rlip depletion in suppressing p53 inactivated cancers, and our findings may yield novel methods for prevention or treatment of cancer in patients with HER2 mutations or tumor HER2 expression.

Protein Phosphatase 2A as a Therapeutic Target in Small Cell Lung Cancer.

Protein phosphatase 2A (PP2A), a serine/threonine phosphatase involved in the regulation of apoptosis, proliferation, and DNA-damage response, is overexpressed in many cancers, including small cell lung cancer (SCLC). Here we report that LB100, a small molecule inhibitor of PP2A, when combined with platinum-based chemotherapy, synergistically elicited an antitumor response both in vitro and in vivo with no apparent toxicity. Using inductively coupled plasma mass spectrometry, we determined quantitatively that sensitization via LB100 was mediated by increased uptake of carboplatin in SCLC cells. Treatment with LB100 alone or in combination resulted in inhibition of cell viability in two-dimensional culture and three-dimensional spheroid models of SCLC, reduced glucose uptake, and attenuated mitochondrial and glycolytic ATP production. Combining LB100 with atezolizumab increased the capacity of T cells to infiltrate and kill tumor spheroids, and combining LB100 with carboplatin caused hyperphosphorylation of the DNA repair marker γH2AX and enhanced apoptosis while attenuating MET signaling and invasion through an endothelial cell monolayer. Taken together, these data highlight the translational potential of inhibiting PP2A with LB100 in combination with platinum-based chemotherapy and immunotherapy in SCLC.

Targeting the mercapturic acid pathway for the treatment of melanoma.

The treatment of metastatic melanoma is greatly hampered by the simultaneous dysregulation of several major signaling pathways that suppress apoptosis and promote its growth and invasion. The global resistance of melanomas to therapeutics is also supported by a highly active mercapturic acid pathway (MAP), which is responsible for the metabolism and excretion of numerous chemotherapy agents. The relative importance of the MAP in melanoma survival was not recognized until demonstrated that B16 melanoma undergoes dramatic apoptosis and regression upon the depletion or inhibition of the MAP transporter protein RLIP. RLIP is a multi-functional protein that couples ATP hydrolysis with the movement of substances. As the rate-limiting step of the MAP, the primary function of RLIP in the plasma membrane is to catalyze the ATP-dependent efflux of unmetabolized drugs and toxins, including glutathione (GSH) conjugates of electrophilic toxins (GS-Es), which are the precursors of mercapturic acids. Clathrin-dependent endocytosis (CDE) is an essential mechanism for internalizing ligand-receptor complexes that promote tumor cell proliferation through autocrine stimulation (Wnt5a, PDGF, ßFGF, TNFα) or paracrine stimulation by hormones produced by fibroblasts (IGF1, HGF) or inflammatory cells (IL8). Aberrant functioning of these pathways appears critical for melanoma cell invasion, metastasis, and evasion of apoptosis. This review focuses on the selective depletion or inhibition of RLIP as a highly effective targeted therapy for melanoma that could cause the simultaneous disruption of the MAP and critical peptide hormone signaling that relies on CDE.