Mutational signatures impact the evolution of anti-EGFR antibody resistance in colorectal cancer.
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ABSTRACT:
SUBMITTER: Woolston A
PROVIDER: S-EPMC7611134 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Metastatic colorectal cancer (mCRC) continues to be counted as a major health problem. The introduction of newer cytotoxics, irinotecan and oxaliplatin, has achieved a significant improvement in survival rates. Novel targeted therapies (bevacizumab, and cetuximab) in combination with most efficient chemotherapy regimens have pushed the median survival beyond the 2-year mark and increased the proportion of patients which could benefit from resection of metastatic lesions. In addition, several studies have proved that the CRC mutation profiles should influence patient selection or stratification in prospective trials. KRAS mutational status represents a paradigm for biomarker development in the era of molecular targeted therapies. The present article is an overview of the most important studies in the development of biomarkers for the optimization of anti-epidermal growth factor receptor (anti-EGFR) treatment in mCRC, beyond KRAS mutations, which is a work in progress. The aim will be to identify molecular markers that might be used to select patients with a higher probability of response to anti-EGFR monoclonal antibodies. Overall the accumulating evidence of the molecular biology of CRC has substantially changed the approach to mCRC treatment and has given clinicians more rational options for treating this illness.
| S-EPMC2839169 | biostudies-other
Project description:BackgroundColorectal cancer (CRC) is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies (both acquired and intrinsic), owing to the amplification or mutation of the KRAS oncogene. However, the mechanism underlying this resistance is incompletely understood.MethodsDLD1 cells with WT (+/-) or KRAS G13D mutant allele were treated with different concentrations of Cetuximab (Cet) or panitumumab (Pab) to study the mechanism underlying the KRAS mutation-induced resistance to anti-EGFR antibodies. The function of AMPK in KRAS mutation-induced resistance to anti-EGFR antibodies in CRC cells, and the regulatory role of Bcl-2 family proteins in DLD1 cells with WT or mutated KRAS upon AMPK activation were investigated. In addition, xenograft tumor models with the nude mouse using DLD1 cells with WT or mutated KRAS were established to examine the effects of AMPK activation on KRAS mutation-mediated anti-EGFR antibody resistance.ResultsHigher levels of AMPK activity in CRC cells with wild-type KRAS treated with anti-EGFR antibody resulted in apoptosis induction. In contrast, CRC cells with mutated KRAS showed lower AMP-activated protein kinase (AMPK) activity and decreased sensitivity to the inhibitory effect of anti-EGFR antibody. CRC cells with mutated KRAS showed high levels of glycolysis and produced an excessive amount of ATP, which suppressed AMPK activation. The knockdown of AMPK expression in CRC cells with WT KRAS produced similar effects to those observed in cells with mutated KRAS and decreased their sensitivity to cetuximab. On the contrary, the activation of AMPK by metformin (Met) or 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) could overcome the KRAS-induced resistance to the anti-EGFR antibody in vivo and in vitro. The activation of AMPK resulted in the inhibition of myeloid cell leukemia 1 (Mcl-1) translation through the suppression of the mammalian target of rapamycin (mTOR) pathway.ConclusionThe results established herein indicate that targeting AMPK is a potentially promising and effective CRC treatment strategy. Video abstract.
| S-EPMC7376720 | biostudies-literature
Project description:Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF1 and non-canonical RAS/RAF aberrations with primary resistance and validated transcriptomic CRC subtypes as non-genetic predictors of benefit. Sixty-four percent of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype at baseline to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PD-L1 and LAG3 immune checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.
| S-EPMC6617392 | biostudies-literature
Project description:Anti-EGFR therapy and antiangiogenic therapies are used alone or in combination with chemotherapies to improve survival in metastatic colorectal cancer. However, it is unknown whether pretreatment with antiangiogenic therapy could impact on the efficacy of anti-EGFR therapy. We selected one hundred and twenty eight patients diagnosed with advanced colorectal cancer with a KRAS and NRAS unmutated tumor. These patients were treated with cetuximab or panitumumab alone or with chemotherapy as second or third-line. Univariate and multivariate Cox model analysis were performed to estimate the effect of a previous bevacizumab regimen on progression free survival and on overall survival during anti-EGFR therapy. In vitro studies using wild type KRAS and NRAS colon cancer cells were performed to evaluate the impact of VEGF-A on cetuximab-induced cell death. The median progression free survival (PFS) during anti-EGFR treatment was significantly different between the bevacizumab group and the non-bevacizumab group (2.8 and 4 months respectively; p = 0.003). The median overall survival from the beginning of the metastatic disease was similar in the two groups (41.3 and 42 months respectively; p = 0.7). In vitro, VEGF-A induced a resistance toward cetuximab cytotoxicity on three KRAS and NRAS wild type colon cancer cell lines in a VEGFR2 and Stat-3-dependent manner. All in all, our clinical data, supported by in vitro procedures, suggest that a previous anti-VEGF therapy decreases anti-EGFR efficacy. Although these results are observed in a limited cohort, they could be taken into consideration for a better strategy of care for patient suffering from metastatic colorectal cancer.
| S-EPMC4891042 | biostudies-literature
Project description:Since 2004, the clinical impact of monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) on patients with metastatic colorectal cancer (MCRC) has been clearly established. The combination of these biological agents with conventional chemotherapy has led to a significant improvement in response rate, progression-free survival and overall survival in first-line as well as in second- or third-line treatment of MCRC. However, the high variability of response and outcome in MCRC patients treated with these anti-EGFR mAbs has highlighted the need of identifying clinical and/or molecular predictive markers to ensure appropriate use of targeted therapies. The presence of somatic KRAS mutations has been clearly identified as a predictive marker of resistance to anti-EGFR in MCRC, and the use of anti-EGFR mAbs is now restricted to patients with no detectable KRAS mutation. Several studies have indicated that amplification of EGFR, overexpression of the EGFR ligands and inactivation of the anti-oncogene TP53 are associated with sensitivity to anti-EGFR mAbs, whereas mutations of BRAF and PIK3CA and loss of PTEN expression are associated with resistance. Besides these somatic variations, germline polymorphisms such as those affecting genes involved in the EGFR pathway or within the immunoglobulin receptors may also modulate response to anti-EGFR mAbs. Until now, all these markers are not completely validated and only KRAS genotyping is mandatory in routine practice for use of the anti-EGFR mAbs in MCRC.
| S-EPMC3008616 | biostudies-literature
Project description:Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR), such as cetuximab and panitumumab, have evolved to important therapeutic options in metastatic colorectal cancer (CRC). However, almost all patients with clinical response to anti-EGFR therapies show disease progression within a few months and little is known about mechanism and timing of resistance evolution. Here we performed whole genome sequencing of plasma DNA (plasma-Seq) from patients treated with anti-EGFR therapy. We demonstrate that development of resistance to anti-EGFR therapies is frequently associated with focal amplifications of KRAS, MET, and ERBB2. However, we also show that focal KRAS amplifications can be acquired in tumor genomes of patients under cytotoxic chemotherapy. Furthermore, we provide evidence that specific chromosomal polysomies, such as overrepresentations of 12p and 7p, harboring KRAS and EGFR, respectively, determine responsiveness to anti-EGFR therapy. In contrast, employing ultra-sensitive deep sequencing of genes associated with anti-EGFR resistance, such as KRAS, BRAF, PIK3CA, and EGFR, we did not observe the occurrence of novel, acquired mutations. Overall, whole-genome plasma DNA sequencing represents a non-invasive blood-based surrogate measure of changes in tumors. As such, plasma-Seq enables the identification of novel mutant clones and may therefore facilitate early adjustments of therapies that may delay or prevent disease progression.
| EGAS00001000582 | EGA
Project description:The now clinically-used anti-epidermal growth factor receptor (EGFR) monoclonal antibodies have demonstrated significant efficacy only in patients with metastatic colorectal cancer (mCRC), with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS). However, no effective treatments for patients with mCRC with KRAS mutated tumors have been approved yet. Therefore, a new strategy for targeting mCRC with KRAS mutated tumors is desired. In the present study, we examined the anti-tumor activities of a novel anti-EGFR monoclonal antibody, EMab-17 (mouse IgG2a, kappa), in colorectal cancer (CRC) cells with the KRAS p.G13D mutation. This antibody recognized endogenous EGRF in CRC cells with or without KRAS mutations, and showed a high sensitivity for CRC cells in flow cytometry, indicating that EMab-17 possesses a high binding affinity to the endogenous EGFR. In vitro experiments showed that EMab-17 exhibited antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity activities against CRC cells. In vivo analysis revealed that EMab-17 inhibited the metastases of HCT-15 and HCT-116 cells in the livers of nude mouse metastatic models, unlike the anti-EGFR monoclonal antibody EMab-51 of subtype mouse IgG1. In conclusion, EMab-17 may be useful in an antibody-based therapy against mCRC with the KRAS p.G13D mutation.
| S-EPMC7504481 | biostudies-literature
Project description:Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the C797S mutation, which impairs the covalent binding between the cysteine residue at position 797 of EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutic strategies to overcome the C797S/T790M/activating-mutation (triple-mutation)-mediated EGFR-TKI resistance. In the present study, we identify brigatinib to be effective against triple-mutation-harbouring cells in vitro and in vivo. Our original computational simulation demonstrates that brigatinib fits into the ATP-binding pocket of triple-mutant EGFR. The structure-activity relationship analysis reveals the key component in brigatinib to inhibit the triple-mutant EGFR. The efficacy of brigatinib is enhanced markedly by combination with anti-EGFR antibody because of the decrease of surface and total EGFR expression. Thus, the combination therapy of brigatinib with anti-EGFR antibody is a powerful candidate to overcome triple-mutant EGFR.
| S-EPMC5355811 | biostudies-literature
Project description:BACKGROUND:The clinical impact of the monoclonal antibody cetuximab targeting the EGFR in colorectal cancer (CRC) is widely recognized. Nevertheless, the onset of cetuximab resistance is a serious issue that limits the effectiveness of this drug in targeted therapies. Unraveling the molecular players involved in cancer resistance is the first step towards the identification of alternative signaling pathways that can be targeted to circumvent resistance mechanisms restoring the efficacy of therapeutic treatments in a tailored manner. METHODS:By applying a nanoLC-MS/MS TMT isobaric labeling-based approach, we have delineated a molecular hallmark of cetuximab-resistance in CRC. RESULTS:We identified macrophage migration inhibitory factor (MIF) as a molecular determinant capable of triggering cancer resistance in sensitive human CRC cells. Blocking the MIF axis in resistant cells by a selective MIF inhibitor restores cell sensitivity to cetuximab. The combined treatment with cetuximab and the MIF inhibitor further enhanced cell growth inhibition in CRC resistant cell lines with a synergistic effect depending on inhibition of key downstream effectors of the MAPK and AKT signaling pathways. CONCLUSIONS:Collectively, our results suggest the association of MIF signaling and its dysregulation to cetuximab drug resistance, paving the way to the development of personalized combination therapies targeting the MIF axis.
| S-EPMC6826402 | biostudies-literature
Project description:To investigate the underlying mechanisms of the inhibitory effects of human anti-human FGFR2IIIc antibody on growth and migration of colorectal cancer cells, we used DNA microarray analysis to examine the cell signaling pathway alterations following the administration of anti-FGFR2IIIc antibody. Cells were plated at a density of 2.5 M-CM-^W 105 cells in a 60-mm dish, and grown overnight. Then 100 M-NM-<g/mL of monoclonal anti-human FGFR2IIIc antibody was added in each dish. For control groups, an equal amount of anti-GFP antibody was added in another dish. After 48 hr, total RNA was isolated from cells. For use in DNA microarray analysis, 50 ng RNA from each group of cells was labeled using the Low Input Quick Amp Labeling kit. Labeled RNA was further purified using the Qiagen RNeasy Mini kit. Labeled cRNA was hybridized to the Agilent human 44k oligonucleotide microarray, and washed using Agilent Gene Expression washing buffer.
2012-06-07 | E-GEOD-38544 | biostudies-arrayexpress