scholarly journals Metabolic Plasticity in Melanoma Progression and Response to Oncogene Targeted Therapies

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5810
Author(s):  
Arwa Alkaraki ◽  
Grant A. McArthur ◽  
Karen E. Sheppard ◽  
Lorey K. Smith
Keyword(s):  
Acquired Resistance ◽  
Genetic Resistance ◽  
Therapy Response ◽  
Early Response ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Metabolic Reprogramming ◽  
Translation Control ◽  
Metabolic Plasticity ◽  
Anti Cancer

Resistance to therapy continues to be a barrier to curative treatments in melanoma. Recent insights from the clinic and experimental settings have highlighted a range of non-genetic adaptive mechanisms that contribute to therapy resistance and disease relapse, including transcriptional, post-transcriptional and metabolic reprogramming. A growing body of evidence highlights the inherent plasticity of melanoma metabolism, evidenced by reversible metabolome alterations and flexibility in fuel usage that occur during metastasis and response to anti-cancer therapies. Here, we discuss how the inherent metabolic plasticity of melanoma cells facilitates both disease progression and acquisition of anti-cancer therapy resistance. In particular, we discuss in detail the different metabolic changes that occur during the three major phases of the targeted therapy response—the early response, drug tolerance and acquired resistance. We also discuss how non-genetic programs, including transcription and translation, control this process. The prevalence and diverse array of these non-genetic resistance mechanisms poses a new challenge to the field that requires innovative strategies to monitor and counteract these adaptive processes in the quest to prevent therapy resistance.

scholarly journals Circulating Tumour DNA Sequencing Identifies a Genetic Resistance-Gap in Colorectal Cancers with Acquired Resistance to EGFR-Antibodies and Chemotherapy

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3736
Author(s):  
Franciele H. Knebel ◽  
Louise J. Barber ◽  
Alice Newey ◽  
Dimitrios Kleftogiannis ◽  
Andrew Woolston ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Large Fraction ◽  
Single Agent ◽  
Acquired Resistance ◽  
Genetic Resistance ◽  
Resistance Mutation ◽  
Resistance Mechanisms ◽  
Wild Type ◽  
Primary Resistance ◽  
Clinical Resistance

Epidermal growth factor receptor antibodies (EGFR-Abs) confer a survival benefit in patients with RAS wild-type metastatic colorectal cancer (mCRC), but resistance invariably occurs. Previous data showed that only a minority of cancer cells harboured known genetic resistance drivers when clinical resistance to single-agent EGFR-Abs had evolved, supporting the activity of non-genetic resistance mechanisms. Here, we used error-corrected ctDNA-sequencing (ctDNA-Seq) of 40 cancer genes to identify drivers of resistance and whether a genetic resistance-gap (a lack of detectable genetic resistance mechanisms in a large fraction of the cancer cell population) also occurs in RAS wild-type mCRCs treated with a combination of EGFR-Abs and chemotherapy. We detected one MAP2K1/MEK1 mutation and one ERBB2 amplification in 2/3 patients with primary resistance and KRAS, NRAS, MAP2K1/MEK1 mutations and ERBB2 aberrations in 6/7 patients with acquired resistance. In vitro testing identified MAP2K1/MEK1 P124S as a novel driver of EGFR-Ab resistance. Mutation subclonality analyses confirmed a genetic resistance-gap in mCRCs treated with EGFR-Abs and chemotherapy, with only 13.42% of cancer cells harboring identifiable resistance drivers. Our results support the utility of ctDNA-Seq to guide treatment allocation for patients with resistance and the importance of investigating further non-canonical EGFR-Ab resistance mechanisms, such as microenvironmentally-mediated resistance. The detection of MAP2K1 mutations could inform trials of MEK-inhibitors in these tumours.

scholarly journals Patient-derived xenografts and organoids model therapy response in prostate cancer

2020 ◽  
Author(s):  
Sofia Karkampouna ◽  
Federico La Manna ◽  
Maria R. De Filippo ◽  
Mirjam Kiener ◽  
Marta De Menna ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Acquired Resistance ◽  
Therapy Response ◽  
Standard Of Care ◽  
Therapy Resistance ◽  
Experimental Models ◽  
Whole Exome ◽  
Transcriptomic Signature ◽  
Treatment Naïve

AbstractTherapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe a novel androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbours BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modelled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.

scholarly journals Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Jacopo Gavini ◽  
Noëlle Dommann ◽  
Manuel O. Jakob ◽  
Adrian Keogh ◽  
Laure C. Bouchez ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Antitumor Effect ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
Resistance Mechanisms ◽  
Chemotherapeutic Agents ◽  
Anti Cancer

Abstract Lysosomal sequestration of anti-cancer compounds reduces drug availability at intracellular target sites, thereby limiting drug-sensitivity and inducing chemoresistance. For hepatocellular carcinoma (HCC), sorafenib (SF) is the first line systemic treatment, as well as a simultaneous activator of autophagy-induced drug resistance. The purpose of this study is to elucidate how combination therapy with the FDA-approved photosensitizer verteporfin (VP) can potentiate the antitumor effect of SF, overcoming its acquired resistance mechanisms. HCC cell lines and patient-derived in vitro and in vivo preclinical models were used to identify the molecular mechanism of action of VP alone and in combination with SF. We demonstrate that SF is lysosomotropic and increases the total number of lysosomes in HCC cells and patient-derived xenograft model. Contrary to the effect on lysosomal stability by SF, VP is not only sequestered in lysosomes, but induces lysosomal pH alkalinization, lysosomal membrane permeabilization (LMP) and tumor-selective proteotoxicity. In combination, VP-induced LMP potentiates the antitumor effect of SF, further decreasing tumor proliferation and progression in HCC cell lines and patient-derived samples in vitro and in vivo. Our data suggest that combination of lysosome-targeting compounds, such as VP, in combination with already approved chemotherapeutic agents could open a new avenue to overcome chemo-insensitivity caused by passive lysosomal sequestration of anti-cancer drugs in the context of HCC.

scholarly journals Patient-derived xenografts and organoids model therapy response in prostate cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sofia Karkampouna ◽  
Federico La Manna ◽  
Andrej Benjak ◽  
Mirjam Kiener ◽  
Marta De Menna ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Acquired Resistance ◽  
Therapy Response ◽  
Standard Of Care ◽  
Therapy Resistance ◽  
Experimental Models ◽  
Whole Exome ◽  
Transcriptomic Signature ◽  
Treatment Naïve

AbstractTherapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.

scholarly journals Determinants of stem cell enrichment in healthy tissues and tumors: implications for non-genetic drug resistance

2019 ◽  
Author(s):  
Lora D. Weiss ◽  
P. van den Driessche ◽  
John S. Lowengrub ◽  
Dominik Wodarz ◽  
Natalia L. Komarova
Keyword(s):  
Drug Resistance ◽  
Stem Cell ◽  
Genetic Resistance ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Resistance Mutations ◽  
Regulatory Processes ◽  
Differentiated Cells ◽  
Somatic Evolution ◽  
Cell Fractions

AbstractDrug resistance is a major challenge for cancer therapy. While resistance mutations are often the focus of investigation, non-genetic resistance mechanisms are also important. One such mechanism is the presence of relatively high fractions of cancer stem cells (CSCs), which have reduced susceptibility to chemotherapy, radiation, and targeted treatments compared to more differentiated cells. The reasons for high CSC fractions (CSC enrichment) are not well understood. Previous experimental and mathematical modeling work identified a particular feedback loop in tumors that can promote CSC enrichment. Here, we use mathematical models of hierarchically structured cell populations to build on this work and to provide a comprehensive analysis of how different feedback regulatory processes that might partially operate in tumors can influence the stem cell fractions during somatic evolution of healthy tissue or during tumor growth. We find that depending on the particular feedback loops that are present, CSC fractions can increase or decrease. We define characteristics of the feedback mechanisms that are required for CSC enrichment to occur, and show how the magnitude of enrichment is determined by parameters. In particular, enrichment requires a reduction in division rates or an increase in death rates with higher population sizes, and the feedback mediators that achieve this can be secreted by either CSCs or by more differentiated cells. The extent of enrichment is determined by the death rate of CSCs, the probability of CSC self-renewal, and by the strength of feedback on cell divisions. Defining these characteristics can guide experimental approaches that aim to screen for and identify feedback mediators that can promote CSC enrichment in specific cancers, which in turn can help understand and overcome the phenomenon of CSC-based therapy resistance.

Cancer Treatment with Liposomes Based Drugs and Genes Co-delivery Systems

2018 ◽  
Vol 25 (28) ◽  
pp. 3319-3332 ◽  
Author(s):  
Chuanmin Zhang ◽  
Shubiao Zhang ◽  
Defu Zhi ◽  
Jingnan Cui
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Synergistic Effects ◽  
Resistance Mechanisms ◽  
Delivery Systems ◽  
Cell Cycle Checkpoints ◽  
Drug Efflux ◽  
Cancer Resistance ◽  
Cancer Models ◽  
Anti Cancer

There are several mechanisms by which cancer cells develop resistance to treatments, including increasing anti-apoptosis, increasing drug efflux, inducing angiogenesis, enhancing DNA repair and altering cell cycle checkpoints. The drugs are hard to reach curative effects due to these resistance mechanisms. It has been suggested that liposomes based co-delivery systems, which can deliver drugs and genes to the same tumor cells and exhibit synergistic anti-cancer effects, could be used to overcome the resistance of cancer cells. As the co-delivery systems could simultaneously block two or more pathways, this might promote the death of cancer cells by sensitizing cells to death stimuli. This article provides a brief review on the liposomes based co-delivery systems to overcome cancer resistance by the synergistic effects of drugs and genes. Particularly, the synergistic effects of combinatorial anticancer drugs and genes in various cancer models employing multifunctional liposomes based co-delivery systems have been discussed. This review also gives new insights into the challenges of liposomes based co-delivery systems in the field of cancer therapy, by which we hope to provide some suggestions on the development of liposomes based co-delivery systems.

scholarly journals The use of hyperpolarised 13C-MRI in clinical body imaging to probe cancer metabolism

2021 ◽  
Author(s):  
Ramona Woitek ◽  
Ferdia A. Gallagher
Keyword(s):  
Cancer Metabolism ◽  
Signal To Noise Ratio ◽  
Response Assessment ◽  
Early Response ◽  
Multiparametric Mri ◽  
Metabolic Reprogramming ◽  
Response To Treatment ◽  
Additional Information ◽  
Positron Emission ◽  
Breast And Prostate Cancer

AbstractMetabolic reprogramming is one of the hallmarks of cancer and includes the Warburg effect, which is exhibited by many tumours. This can be exploited by positron emission tomography (PET) as part of routine clinical cancer imaging. However, an emerging and alternative method to detect altered metabolism is carbon-13 magnetic resonance imaging (MRI) following injection of hyperpolarised [1-13C]pyruvate. The technique increases the signal-to-noise ratio for the detection of hyperpolarised 13C-labelled metabolites by several orders of magnitude and facilitates the dynamic, noninvasive imaging of the exchange of 13C-pyruvate to 13C-lactate over time. The method has produced promising preclinical results in the area of oncology and is currently being explored in human imaging studies. The first translational studies have demonstrated the safety and feasibility of the technique in patients with prostate, renal, breast and pancreatic cancer, as well as revealing a successful response to treatment in breast and prostate cancer patients at an earlier stage than multiparametric MRI. This review will focus on the strengths of the technique and its applications in the area of oncological body MRI including noninvasive characterisation of disease aggressiveness, mapping of tumour heterogeneity, and early response assessment. A comparison of hyperpolarised 13C-MRI with state-of-the-art multiparametric MRI is likely to reveal the unique additional information and applications offered by the technique.

scholarly journals Metabolic Anti-Cancer Effects of Melatonin: Clinically Relevant Prospects

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3018
Author(s):  
Marek Samec ◽  
Alena Liskova ◽  
Lenka Koklesova ◽  
Kevin Zhai ◽  
Elizabeth Varghese ◽  
...  
Keyword(s):  
Cancer Metabolism ◽  
Glucose Transporter ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Lactate Production ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Effective Prevention ◽  
Anti Cancer ◽  
Glucose 6 Phosphate Dehydrogenase

Metabolic reprogramming characterized by alterations in nutrient uptake and critical molecular pathways associated with cancer cell metabolism represents a fundamental process of malignant transformation. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone secreted by the pineal gland. Melatonin primarily regulates circadian rhythms but also exerts anti-inflammatory, anti-depressant, antioxidant and anti-tumor activities. Concerning cancer metabolism, melatonin displays significant anticancer effects via the regulation of key components of aerobic glycolysis, gluconeogenesis, the pentose phosphate pathway (PPP) and lipid metabolism. Melatonin treatment affects glucose transporter (GLUT) expression, glucose-6-phosphate dehydrogenase (G6PDH) activity, lactate production and other metabolic contributors. Moreover, melatonin modulates critical players in cancer development, such as HIF-1 and p53. Taken together, melatonin has notable anti-cancer effects at malignancy initiation, progression and metastasing. Further investigations of melatonin impacts relevant for cancer metabolism are expected to create innovative approaches supportive for the effective prevention and targeted therapy of cancers.

scholarly journals Current Trends in Non-Invasive Imaging of Interactions in the Liver Tumor Microenvironment Mediated by Tumor Metabolism

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3645
Author(s):  
Isabel Theresa Schobert ◽  
Lynn Jeanette Savic
Keyword(s):  
Tumor Microenvironment ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Imaging Techniques ◽  
Treatment Strategies ◽  
Tumor Metabolism ◽  
Resistance Mechanisms ◽  
Metabolic Reprogramming ◽  
Non Invasive

With the increasing understanding of resistance mechanisms mediated by the metabolic reprogramming in cancer cells, there is a growing clinical interest in imaging technologies that allow for the non-invasive characterization of tumor metabolism and the interactions of cancer cells with the tumor microenvironment (TME) mediated through tumor metabolism. Specifically, tumor glycolysis and subsequent tissue acidosis in the realms of the Warburg effect may promote an immunosuppressive TME, causing a substantial barrier to the clinical efficacy of numerous immuno-oncologic treatments. Thus, imaging the varying individual compositions of the TME may provide a more accurate characterization of the individual tumor. This approach can help to identify the most suitable therapy for each individual patient and design new targeted treatment strategies that disable resistance mechanisms in liver cancer. This review article focuses on non-invasive positron-emission tomography (PET)- and MR-based imaging techniques that aim to visualize the crosstalk between tumor cells and their microenvironment in liver cancer mediated by tumor metabolism.

scholarly journals Efficacy of the CDK4/6 Dual Inhibitor Abemaciclib in EGFR-Mutated NSCLC Cell Lines with Different Resistance Mechanisms to Osimertinib

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 6
Author(s):  
Silvia La Monica ◽  
Claudia Fumarola ◽  
Daniele Cretella ◽  
Mara Bonelli ◽  
Roberta Minari ◽  
...  
Keyword(s):  
Cell Lines ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Resistant Cell ◽  
Nsclc Cell ◽  
Dual Inhibitor ◽  
Nsclc Patients ◽  
Egfr Mutated

Abemaciclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6 that inhibits the transition from the G1 to the S phase of the cell cycle by blocking downstream CDK4/6-mediated phosphorylation of Rb. The effects of abemaciclib alone or combined with the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib were examined in a panel of PC9 and HCC827 osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines carrying EGFR-dependent or -independent mechanisms of intrinsic or acquired resistance. Differently from sensitive cells, all the resistant cell lines analyzed maintained p-Rb, which may be considered as a biomarker of osimertinib resistance and a potential target for therapeutic intervention. In these models, abemaciclib inhibited cell growth, spheroid formation, colony formation, and induced senescence, and its efficacy was not enhanced in the presence of osimertinib. Interestingly, in osimertinib sensitive PC9, PC9T790M, and H1975 cells the combination of abemaciclib with osimertinib significantly inhibited the onset of resistance in long-term experiments. Our findings provide a preclinical support for using abemaciclib to treat resistance in EGFR mutated NSCLC patients progressed to osimertinib either as single treatment or combined with osimertinib, and suggest the combination of osimertinib with abemaciclib as a potential approach to prevent or delay osimertinib resistance in first-line treatment.

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