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Anti-Metastatic Activity of an Anti-EGFR Monoclonal Antibody against Metastatic Colorectal Cancer with KRAS p.G13D Mutation.

ABSTRACT: 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.

SUBMITTER: Ohishi T

PROVIDER: S-EPMC7504481 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Anti-Metastatic Activity of an Anti-EGFR Monoclonal Antibody against Metastatic Colorectal Cancer with KRAS p.G13D Mutation.

Ohishi Tomokazu T Kato Yukinari Y Kaneko Mika K MK Ohba Shun-Ichi SI Inoue Hiroyuki H Harakawa Akiko A Kawada Manabu M

International journal of molecular sciences 20200821 17

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 ...[more]

PMID: 32839411

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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.

Project description:BACKGROUND: BRAF mutation has been investigated as a prognostic factor in metastatic colorectal cancer (mCRC) undergoing anti-EGFR monoclonal antibodies (moAbs), but current results are still inconclusive. The aim of this meta-analysis was to evaluate the relationship between BRAF mutation status and the prognosis of mCRC patients treated with moAbs. METHODS: Eligible studies were identified by systematically searching Pubmed, the Cochrane Library, Web of Knowledge, and OVID. Risk ratio (RR) for overall response rate (ORR), Hazard ratios (HRs) for Progression free survival (PFS) and Overall survival (OS) were extracted or calculated. Prespecified subgroup analyses were conducted in KRAS wild-type and in different study types. The source of between-trial variation was explored by sensitivity analyses. Quality assessment was conducted by the Hayden's criteria. RESULTS: A total of twenty one trials including 5229 patients were identified for the meta-analysis. 343 patients displayed BRAF mutations of 4616 (7.4%) patients with known BRAF status. Patients with BRAF wild-type (WT) showed decreased risks of progression and death with an improved PFS(HR 0.38, 95% confidence intervals 0.29-0.51) and an improved OS (HR 0.35 [0.29-0.42]), compared to BRAF mutant. In KRAS WT population, there were even larger PFS benefit (HR 0.29[0.19,0.43]) and larger OS benefit (HR 0.26 [0.20,0.35]) in BRAF WT. A response benefit for BRAF WT was observed (RR 0.31[0.18,0.53]) in KRAS WT patients, but not observed in unselected patients (RR 0.76 [0.43-1.33]). The results were consistent in the subgroup analysis of different study types. Heterogeneity between trials decreased in the subgroup and explained by sensitivity analysis. No publication bias of ORR, PFS and OS were detected. CONCLUSIONS: The results indicate that BRAF mutant is a predictive biomarker for poor prognosis in mCRC patients undergoing anti-EGFR MoAbs therapy, especially in KRAS WT patients. Additional large prospective trials are required to confirm the predictive role of BRAF status.

Project description:BackgroundAn over-expression of the epidermal growth factor receptor (EGFR) has been observed in colorectal cancer and is associated with aggressive disease and poor prognosis. SCT200 is a newly developed recombinant, fully humanized, anti-EGFR monoclonal antibody. This study aimed to evaluate its safety, tolerability, pharmacokinetics (PK), and efficacy in patients with wild-type KRAS/NRAS/BRAF metastatic colorectal cancer (mCRC). METHODS: This phase I study comprising dose-escalation phase and dose-expansion phase. SCT200 was administrated intravenously to groups of three to six patients. An every 3-week dosing cycle (0.5-15.0 mg/kg) and multiple dosing schedule were evaluated. Blood samples were collected at preset intervals for PK assessment, radiological imaging was used for efficacy assessment, and continuous safety monitoring was performed in each group during the study. RESULTS: From December 16, 2014 to December 31, 2018, fifty-six patients with wild-type KRAS/NRAS/BRAF mCRC receiving ≥ 1 dose of SCT200 were evaluated. Among them, 44.6% (25/56) of the patients failed at least two prior lines of chemotherapy. No dose-limiting toxicities occurred in any group. All of the patients experienced treatment-emergent adverse events (TEAEs). 96.4% (54/56) of patients experienced treatment-related adverse events (TRAEs), and 26.8% (15/56) of patients with Grade ≥ 3 TRAEs. No serious TRAEs were observed. The most common TRAEs were dermotoxicity and hypomagnesemia. PK analysis showed non-linear PK in the range of 0.5 - 8.0 mg/kg of single dose SCT200, the clearance decreased, and the elimination half-life (T1/2) prolonged following dose increase. In the multiple-dose period, the clearance decreased, peak concentration increased, and T1/2 prolonged during prolonged drug administration, and a steady state was reached after five consecutive dose of 6.0 mg/kg quaque week (QW). The objective response rate (ORR) was 30.4% (17/56, 95% confidence interval [CI], 18.8%-44.1%). The ORR in the dose-expansion group (6.0 mg/kg QW) was 48.0% (12/25, 95% CI, 27.8%-68.7%), the median progression-free survival was 5.2 months (95%CI, 3.6-5.5), and the median overall survival was 20.2 months (95%CI, 12.1-not reached).ConclusionsSCT200 showed favorable safety, PK profile, and preliminary efficacy for patients with wild-type KRAS/NRAS/BRAF mCRC.Trial registrationThis study was registered with ClinicalTrials.gov ( NCT02211443 ).

Dataset Information

Anti-Metastatic Activity of an Anti-EGFR Monoclonal Antibody against Metastatic Colorectal Cancer with KRAS p.G13D Mutation.

Publications

Anti-Metastatic Activity of an Anti-EGFR Monoclonal Antibody against Metastatic Colorectal Cancer with <i>KRAS</i> p.G13D Mutation.

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