Transcriptomics changes in liver metastatic biopsies of colorectal carcinoma between pre-treated and acquired resistance to Cetuximab
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE84270 | GEO | 2019/06/20
REPOSITORIES: GEO
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Project description:Two patients who were newly diagnosed and pathologically confirmed metastatic colorectal cancer were screened for eligibility between August 2011 and December 2013 in Affiliated Hospital, Academy of Military Medical Sciences. They were treated with Cetuximab in combination with FOLFOX regimen and obtained continuous partial responses in more than six months. CT scans of liver lesions were performed every two to eight weeks. The four biopsies were evaluated by two pathologists and were confirmed that the tumor purities were greater than 50%. Each biopsy was subjected to high-throughput RNA and small RNA sequencing to obtain expression profiles of genes and miRNAs.
2019-06-20 | GSE84269 | GEO
Project description:Two patients who were newly diagnosed and pathologically confirmed metastatic colorectal cancer were screened for eligibility between August 2011 and December 2013 in Affiliated Hospital, Academy of Military Medical Sciences. They were treated with Cetuximab in combination with FOLFOX regimen and obtained continuous partial responses in more than six months. CT scans of liver lesions were performed every two to eight weeks. The four biopsies were evaluated by two pathologists and were confirmed that the tumor purities were greater than 50%. Each biopsy was subjected to high-throughput RNA and small RNA sequencing to obtain expression profiles of genes and miRNAs.
2019-06-20 | GSE84267 | GEO
Project description:Transcriptomics changes in liver metastatic biopsies of colorectal carcinoma between pre-treated and acquired resistance to Cetuximab
| PRJNA328492 | ENA
Project description:Purpose: Mutations in KRAS are considered to be the main drivers of acquired resistance to epidermal growth factor receptor (EGFR) blockade in patients with metastatic colorectal cancer (mCRC). However, the potential role of other genes downstream of the EGFR signaling pathway in conferring acquired resistance has not been extensively investigated.Experimental Design: Using circulating tumor DNA (ctDNA) from patients with mCRC and with acquired cetuximab resistance, we developed a targeted amplicon ultra-deep sequencing method to screen for low-abundance somatic mutations in a panel of genes that encode components of the EGFR signaling pathway. Mutations with significantly increased variant frequencies upon disease progression were selected by using quartile analysis. The functional consequences of the identified mutations were validated in cultured cells.Results: We analyzed 32 patients with acquired cetuximab resistance in a development cohort. Of them, seven (22%) carried five novel PIK3CA mutations, whereas eight (25%) carried previously reported KRAS mutations. Functional studies showed that novel PIK3CA mutations (all in exon 19; p.K944N, p.F930S, p.V955G, p.V955I, and p.K966E) promote cell viability in the presence of cetuximab. Only one novel PIK3CA mutation (p.K944N) was verified in one of the 27 patients with acquired resistance in a validation cohort, simultaneous KRAS and PIK3CA hotspot mutations were detected in two patients. Among the above 59 acquired resistance patients, those with PIK3CA or RAS mutations detected in ctDNA showed a pronounced decrease in progression-free survival than patients with no mutation.Conclusions: The PIK3CA mutations may potentially contribute to acquired cetuximab resistance in patients with mCRC. Clin Cancer Res; 23(16); 4602-16. ©2017 AACR.
| S-EPMC5559326 | biostudies-literature
Project description:Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4-RET and LMNA-NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.
| S-EPMC6814827 | biostudies-other
Project description:Background/aimCetuximab in combination with chemotherapy is recommended as first-line therapy for metastatic colorectal cancer (mCRC) with wild-type RAS. However, drug resistance to cetuximab exists widely in mCRC and reduces the prognosis of patients. Although some genomic alterations have been demonstrated to drive acquired resistance to cetuximab, the overall compendium of inherent molecular mechanisms is still incomplete.Materials and methodsFour liver metastasis biopsies were collected from two mCRC patients who were treated with cetuximab in combination with 5-fluororacil plus leucovorin and oxaliplatin (FOLFOX) regimen.ResultsTranscriptomic analysis revealed global gene expression alterations between paired samples prior to treatment and after acquired resistance. Further bioinformatics analysis discovered differentially expressed protein-coding genes/lncRNAs/miRNAs, potential miRNA-mRNA regulatory networks and lncRNA-mRNA competing endogenous RNA network, which may be potential biomarkers or play roles during the process of acquired resistance to cetuximab.ConclusionOur study contributes to deciphering the molecular mechanisms of acquired resistance to cetuximab.
| S-EPMC6542644 | biostudies-literature
Project description:Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4–RET and LMNA–NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.
2019-09-21 | E-MTAB-8340 | biostudies-arrayexpress
Project description:Approximately 45% of metastatic colorectal cancer (mCRC) patients with wild-type KRAS exon 2 are resistant to cetuximab treatment. We set out to identify additional genetic markers that might predict the response to cetuximab treatment. Fifty-three wild-type KRAS exon 2 mCRC patients were treated with cetuximab/irinotecan-based chemotherapy as a first- or third-line therapy. The mutational statuses of 10 EGFR pathway genes were analyzed in primary tumors using next-generation sequencing. BRAF, PIK3CA, KRAS (exons 3 and 4), NRAS, PTEN, and AKT1 mutations were detected in 6, 6, 5, 4, 1, and 1 patient, respectively. Four of the BRAF mutations were non-V600 variants. Four tumors harbored multiple co-existing (complex) mutations. All patients with BRAF mutations or complex mutation patterns were cetuximab non-responders. All patients but one harboring KRAS, NRAS, or BRAF mutations were non-responders. Mutations in any one of these three genes were associated with a poor response rate (7.1%) and reduced survival (PFS = 8.0 months) compared to wild-type patients (74.4% and 11.6 months). Our data suggest that KRAS, NRAS, and BRAF mutations predict response to cetuximab treatment in mCRC patients.
| S-EPMC5008360 | biostudies-literature
Project description:Resistance to epidermal growth factor receptor (EGFR) targeted monoclonal antibody therapy represents a clinical challenge in patients suffered from RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, the molecular mechanisms and key factors conferring this resistance are largely unknown. Forkhead transcription factors of the O class 3a (FoxO3a), an important regulator of cell survival, has been reported with dual functions in tumor recently. In this study, we found that FoxO3a was highly expressed in cetuximab resistant CRC tissues compared with cetuximab sensitive tissues. We therefore further analyzed its function in induced cetuximab resistant RAS-WT CRC cells (Caco2-CR) and intrinsic resistant cells with BRAF mutation (HT29). We found that FoxO3a was significantly up-regulated in Caco2-CR as well as in cetuximab treated HT29 cells. Knockdown of FoxO3a could sensitize these cells to cetuximab treatment with reduced cell proliferation and migration ability. Further, biochemical experiments demonstrated that FoxO3a directly bind to c-Myc promoter and activated the transcription of the c-Myc gene, thus participated in regulating of c-Myc downstream genes, including ACO2, LARS2, MRPL12 and PKM2 in these resistant cells. Moreover, knockdown of c-Myc elevated cell apoptosis to cetuximab treatment and suppressed cell proliferation and migration ability consistently. Altogether, our study indicates that FoxO3a might be a key regulator in cetuximab resistance through up-regulating c-Myc in colorectal cancer targeted therapy.
| S-EPMC5348362 | biostudies-literature
Project description:AimTo evaluate whether PCR-reverse sequence-specific oligonucleotide can examine the concordance between liquid biopsy and metastatic lesions with acquired resistance.Materials & methodsWe 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.ResultsIn 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.ConclusionLiquid biopsy based on PCR-reverse sequence-specific oligonucleotide is a successful procedure for capturing acquired mutations with precise information on the RAS mutational spectrum.
| S-EPMC8609982 | biostudies-literature