scholarly journals Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer

Cancer Cell ◽  
2019 ◽  
Vol 36 (1) ◽  
pp. 35-50.e9 ◽  
Author(s):  
Andrew Woolston ◽  
Khurum Khan ◽  
Georgia Spain ◽  
Louise J. Barber ◽  
Beatrice Griffiths ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Landscape Evolution ◽  
Therapy Resistance

Lipocalin 2 expression promotes tumor progression and therapy resistance by inhibiting ferroptosis in colorectal cancer

2021 ◽  
Author(s):  
Nazia Chaudhary ◽  
Bhagya Shree Choudhary ◽  
Sanket Girish Shah ◽  
Nileema Khapare ◽  
Nehanjali Dwivedi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Progression ◽  
Therapy Resistance ◽  
Lipocalin 2

scholarly journals MicroRNA-Assisted Hormone Cell Signaling in Colorectal Cancer Resistance

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 39
Author(s):  
Crescenzo Massaro ◽  
Elham Safadeh ◽  
Giulia Sgueglia ◽  
Hendrik G. Stunnenberg ◽  
Lucia Altucci ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Therapy Resistance ◽  
Disease Recurrence ◽  
Hormone Signaling ◽  
Cancer Resistance ◽  
Comprehensive Overview ◽  
Substantial Progress

Despite substantial progress in cancer therapy, colorectal cancer (CRC) is still the third leading cause of cancer death worldwide, mainly due to the acquisition of resistance and disease recurrence in patients. Growing evidence indicates that deregulation of hormone signaling pathways and their cross-talk with other signaling cascades inside CRC cells may have an impact on therapy resistance. MicroRNAs (miRNAs) are small conserved non-coding RNAs thatfunction as negative regulators in many gene expression processes. Key studies have identified miRNA alterations in cancer progression and drug resistance. In this review, we provide a comprehensive overview and assessment of miRNAs role in hormone signaling pathways in CRC drug resistance and their potential as future targets for overcoming resistance to treatment.

scholarly journals KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer

Cancer Cell ◽  
2019 ◽  
Vol 35 (4) ◽  
pp. 559-572.e7 ◽  
Author(s):  
Wenting Liao ◽  
Michael J. Overman ◽  
Adam T. Boutin ◽  
Xiaoying Shang ◽  
Di Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Suppression ◽  
Immune Therapy ◽  
Therapy Resistance

Treatment monitoring of metastatic colorectal cancer by quantification and genotyping of mutated KRAS in circulating cell-free DNA.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15037-e15037 ◽  
Author(s):  
Thomas Seufferlein ◽  
Daniel Schwerdel ◽  
Hanna Welz ◽  
Ralf Marienfeld ◽  
Stefan A. Schmidt ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mutational Analysis ◽  
Early Stage ◽  
Therapy Monitoring ◽  
Stage Iv ◽  
Therapy Resistance ◽  
Disease Monitoring ◽  
Liquid Biopsies ◽  
Kras Mutations ◽  
Non Invasive

e15037 Background: Treatment of stage IV colorectal cancer (mCRC) has made substantial progress over the last years but therapy monitoring still is in its early stage. A facile, non-invasive, repeatable assessment of the mutational state of a given tumor even during treatment could constitute a desirable biomarker for therapy stratification and disease monitoring. "Liquid biopsies" analyzing circulating free and circulating tumor DNA (cfDNA/ctDNA) from patients’ blood have been proposed as a a simple, non-invasive method that could fulfil this requirement. Methods: 27 patients with histologically confirmed mCRC were enrolled into a treatment surveillance cohort. For the analysis of concordance between tumor tissue DNA and cfDNA we analyzed 40 tissue and blood pairs from therapy naïve patients regarding their KRAS mutation status. The course of cfDNA values combined with targeted genotyping of KRAS mutations were assessed during several palliative chemotherapeutic regimens. cfDNA data were correlated with clinical parameters to establish its prognostic and predictive value. Results: Baseline cfDNA levels allow to significantly differentiate mCRC from healthy controls (14.23 ± 6.33 ng/ml vs. 2.60 ± 1.59 ng/ml; p < 0.0001). cfDNA values at baseline in therapy naïve patients correlate well with tumor burden (p < 0.05) and CEA levels (p < 0.05). cfDNA values significantly increased upon disease progression during 1st (p < 0.01) and 2nd line (p < 0.05) treatment, enabling a non-invasive disease monitoring approach. Moreover, there was a significant correlation between the cfDNA levels upon treatment and progression-free survival (p < 0.05). In addition, our data show that KRAS genotyping of cfDNA under therapy is feasible (80% blood-tissue concordance) and might benefit the patient due to early detection of therapy resistance. Conclusions: Repetitive quantitative and mutational analysis of cfDNA is likely to complement current diagnostic standards in stage IV CRC over the whole continuum of treatment.

scholarly journals Similar but different: distinct roles for KRAS and BRAF oncogenes in colorectal cancer development and therapy resistance

Oncotarget ◽  
2015 ◽  
Vol 6 (25) ◽  
pp. 20785-20800 ◽  
Author(s):  
Markus Morkel ◽  
Pamela Riemer ◽  
Hendrik Bläker ◽  
Christine Sers
Keyword(s):  
Colorectal Cancer ◽  
Therapy Resistance ◽  
Cancer Development

scholarly journals Fusobacterium nucleatum facilitates cetuximab resistance in colorectal cancer via the PI3K/AKT and JAK/STAT3 pathways

2020 ◽  
Author(s):  
Hu Han ◽  
Yan Li ◽  
Wan Qin ◽  
Lu Wang ◽  
Han Yin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Fusobacterium Nucleatum ◽  
Therapy Resistance ◽  
Tumor Burden ◽  
Wild Type ◽  
Poor Clinical Outcome ◽  
Functional Studies ◽  
Cetuximab Therapy

AbstractInfectious pathogens contribute to about 20% of the total tumor burden. Fusobacterium nucleatum (Fn) has been associated with the initiation, progression, and therapy resistance in colorectal cancer (CRC). The over-abundance of Fn has been observed in patients with right-sided CRC than in those with left-sided CRC. While the KRAS/NRAS/BRAF wild-type status of the CRC conferred better response to cetuximab in patients with left-sided CRC than with right-sided CRC. However, treatment failure remains the leading cause of tumor relapse and poor clinical outcome in patients with CRC. Here, we have studied the association of Fn to cetuximab resistance. Our functional studies indicate that Fn facilitates resistance of CRC to cetuximab in vitro and in vivo. Moreover, Fn was found to target the PI3K/AKT and JAK/STAT3 pathways, which altered the response to cetuximab therapy. Therefore, assessing the levels and targeting Fn and the associated signaling pathways may allow modulating the treatment regimen and improve prognoses of CRC patients.

scholarly journals Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Anna-Lena Scherr ◽  
Andreas Mock ◽  
Georg Gdynia ◽  
Nathalie Schmitt ◽  
Christoph E. Heilig ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Ex Vivo ◽  
Combined Treatment ◽  
Therapy Resistance ◽  
Sequencing Analysis ◽  
Protein Activity ◽  
Highly Active ◽  
Promising Therapeutic Target ◽  
Induced Apoptosis

Abstract Since metastatic colorectal cancer (CRC) is a leading cause of cancer-related death, therapeutic approaches overcoming primary and acquired therapy resistance are an urgent medical need. In this study, the efficacy and toxicity of high-affinity inhibitors targeting antiapoptotic BCL-2 proteins (BCL-2, BCL-XL, and MCL-1) were evaluated. By RNA sequencing analysis of a pan-cancer cohort comprising >1500 patients and subsequent prediction of protein activity, BCL-XL was identified as the only antiapoptotic BCL-2 protein that is overactivated in CRC. Consistently, pharmacologic and genetic inhibition of BCL-XL induced apoptosis in human CRC cell lines. In a combined treatment approach, targeting BCL-XL augmented the efficacy of chemotherapy in vitro, in a murine CRC model, and in human ex vivo derived CRC tissue cultures. Collectively, these data show that targeting of BCL-XL is efficient and safe in preclinical CRC models, observations that pave the way for clinical translation.

scholarly journals Immune Resistance and EGFR Antagonists in Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1089 ◽  
Author(s):  
Giordano ◽  
Remo ◽  
Porras ◽  
Pancione
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Therapy Resistance ◽  
Cell Interaction ◽  
Molecular Alterations ◽  
Immune Resistance ◽  
Epidermal Growth ◽  
Mechanistic Basis

: Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy in patients with RAS wild type metastatic colorectal cancer (mCRC) has revolutionized the treatment of CRC, but with less results than initially envisaged. In recent years, the discovery of multiple pathways leading to the escape from anti-EGFR therapy has revealed an enormous complexity and heterogeneity of human CRC due to the intrinsic genomic instability and immune/cancer cell interaction. Therefore, understanding the mechanistic basis of acquired resistance to targeted therapies represents a major challenge to improve the clinical outcomes of patients with CRC. The latest findings strongly suggest that complex molecular alterations coupled with changes of the immune tumor microenvironment may substantially contribute to the clinical efficacy of EGFR antagonist. In this review, we discuss the most recent findings that contribute to both primary and acquired anti-EGFR therapy resistance. In addition, we analyze how strategies aiming to enhance the favorable effects in the tumor microenvironment may contribute to overcome resistance to EGFR therapies.

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