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.

KLF4 p.A472D mutation: An acquired resistant mutation to cetuximab in colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15077-e15077
Author(s):  
Liu Yang ◽  
Jiahong Jiang ◽  
Lianpeng Chang ◽  
Yaping Xu ◽  
Chao Ni ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Function Analysis ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Sequencing Analysis ◽  
Kras Mutations ◽  
Target Capture ◽  
Epidermal Growth

e15077 Background: With the increase of treatment course, acquired resistance of epidermal growth factor receptor (EGFR) blockade is inevitable in patients with metastatic colorectal cancer (mCRC). KRAS mutations have been considered to be primary drivers of this acquired resistance; however, the potential function of other genes has not been extensively investigated. Methods: This study included 17 mCRC patients with acquired cetuximab resistance, and mutations in circulating tumor DNA (ctDNA) from plasma samples were identified using target-capture deep sequencing. Analysis of mutational prevalence in ctDNA, three CRC tissue-based datasets and one ctDNA dataset was performed. Mutation predicted with significant effect on acquired resistance was selected and the functional analysis was validated in CRC cells. Results: The prevalence of mutations identified in ctDNA was consistent with CRC tissue-based and ctDNA datasets. Clonal analysis revealed that 41.2% of patients were positive for at least one subclonal. Multiply resistance mechanisms of cetuximab were co-existed in individual patient, with one of them even harbored nine distinct mutations. In particularly, function analysis of Krüppel-like factor 4 (KLF4) mutation p.A472D revealed increased cetuximab resistance in CRC cells, which was associated with the increased phosphorylation of downstream EGFR signaling proteins. Conclusions: The KLF4 mutation p.A472D contributes to acquired cetuximab resistance in patients with mCRC and it may serve as a new biomarker useful in clinical application. Monitoring somatic mutations related to acquired cetuximab resistance in mCRC patients through ctDNA is an appropriate means of providing real-time insights useful for clinical reference and treatment planning.

scholarly journals Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer

2018 ◽  
Author(s):  
Andrew Woolston ◽  
Khurum Khan ◽  
Georgia Spain ◽  
Louise J Barber ◽  
Beatrice Griffiths ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Prospective Trial ◽  
Genetic Resistance ◽  
Growth Factor Receptor ◽  
Therapy Resistance ◽  
Wild Type ◽  
Epidermal Growth ◽  
Novel Associations

AbstractAnti-epidermal growth factor receptor (EGFR) antibodies (anti-EGFR-Ab) are effective in a subgroup of patients with metastatic colorectal cancer (CRC). We applied genomic and transcriptomic analyses to biopsies from 35 RAS wild-type CRCs treated with the anti-EGFR-Ab cetuximab in a prospective trial to interrogate the molecular resistance landscape. This validated transcriptomic CRC-subtypes as predictors of cetuximab benefit; identified novel associations of NF1-inactivation and non-canonical RAS/RAF-aberrations with primary progression; and of FGF10- and non-canonical BRAF-aberrations with AR. No genetic resistance drivers were detected in 64% of AR biopsies. The majority of these had switched from the cetuximab-sensitive CMS2-subtype pretreatment to the fibroblast- and growth factor-rich CMS4-subtype at progression. Fibroblast supernatant conferred cetuximab resistance in vitro, together supporting subtype-switching as a novel mechanism of AR. Cytotoxic immune infiltrates and immune-checkpoint expression increased following cetuximab responses, potentially providing opportunities to treat CRCs with molecularly heterogeneous AR with immunotherapy.

scholarly journals Non-Coding RNAs Regulate the Resistance to Anti-EGFR Therapy in Colorectal Cancer

2022 ◽  
Vol 11 ◽  
Author(s):  
Jinjin Chu ◽  
Xianzhu Fang ◽  
Zhonghou Sun ◽  
Linlin Gai ◽  
Wenqing Dai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Therapy Resistance ◽  
Circular Rnas ◽  
Free Survival ◽  
Epidermal Growth ◽  
Non Coding Rnas ◽  
And Function ◽  
Molecular Targeting Agents

Colorectal cancer (CRC) is the third prevalent cancer worldwide, the morbidity and mortality of which have been increasing in recent years. As molecular targeting agents, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (McAbs) have significantly increased the progression-free survival (PFS) and overall survival (OS) of metastatic CRC (mCRC) patients. Nevertheless, most patients are eventually resistant to anti-EGFR McAbs. With the intensive study of the mechanism of anti-EGFR drug resistance, a variety of biomarkers and pathways have been found to participate in CRC resistance to anti-EGFR therapy. More and more studies have implicated non-coding RNAs (ncRNAs) primarily including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are widely involved in tumorigenesis and tumor progression. They function as essential regulators controlling the expression and function of oncogenes. Increasing data have shown ncRNAs affect the resistance of molecular targeted drugs in CRC including anti-EGFR McAbs. In this paper, we have reviewed the advance in mechanisms of ncRNAs in regulating anti-EGFR McAbs therapy resistance in CRC. It provides insight into exploring ncRNAs as new molecular targets and prognostic markers for CRC.

scholarly journals The Winding Roadmap of Biomarkers toward Clinic: Lessons from Predictors of Resistance to Anti-EGFRs in Metastatic Colorectal Cancer

2018 ◽  
Vol 19 (8) ◽  
pp. 2298 ◽  
Author(s):  
Carlotta Antoniotti ◽  
Elena Ongaro ◽  
Alfredo Falcone ◽  
Chiara Cremolini
Keyword(s):  
Colorectal Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Monoclonal Antibodies ◽  
Clinical Practice ◽  
Metastatic Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Molecular Alterations ◽  
Epidermal Growth ◽  
Molecular Landscape ◽  
To Receive

In the evolving molecular landscape of metastatic colorectal cancer, optimizing available tools to select patients to receive anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies is a modern challenge of colorectal oncologists. Several molecular biomarkers have been investigated in recent years as potential predictors of resistance to anti-EGFR agents in preclinical and clinical retrospective series. Nevertheless, none of them have been implemented in clinical practice due to the lack of a formal prospective demonstration. Here, we propose a literature review of molecular alterations associated with resistance to anti-EGFRs, underlining the reasons why their roadmap from laboratories to clinics was prematurely halted.

scholarly journals Concordance of acquired mutations between metastatic lesions and liquid biopsy in metastatic colorectal cancer

2021 ◽  
Author(s):  
Fumitaka Taniguchi ◽  
Akihiro Nyuya ◽  
Toshiaki Toshima ◽  
Kazuya Yasui ◽  
Yoshiko Mori ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Wild Type ◽  
Metastatic Lesions ◽  
Reverse Sequence ◽  
Epidermal Growth ◽  
Receptor Antibodies

Aim: To evaluate whether PCR-reverse sequence-specific oligonucleotide can examine the concordance between liquid biopsy and metastatic lesions with acquired resistance. Materials & methods: We examined acquired mutations in chemoresistant lesions and blood obtained from four patients with RAS wild-type metastatic colorectal cancer who underwent treatment with anti-epidermal growth factor receptor antibodies. Results: In one patient, metastatic lesions harbored diverse acquired mutations in KRAS in all seven metastases; the two acquired mutations were detectable in blood collected after the patient acquired resistance. None of the other patients exhibited liquid biopsy mutations, except one, with a BRAF mutation confirmed in primary tumor and peritoneal dissemination. Conclusion: Liquid biopsy based on PCR-reverse sequence-specific oligonucleotide is a successful procedure for capturing acquired mutations with precise information on the RAS mutational spectrum.

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