Cetuximab-Induced MET Activation Acts as a Novel Resistance Mechanism in Colon Cancer Cells

Song, Na; Liu, Shizhou; Zhang, Jingdong; Liu, Jing; Xu, Ling; Liu, Yunpeng; Qu, Xiujuan

doi:10.3390/ijms15045838

Cited by 34 publications

(38 citation statements)

References 26 publications

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“…It is well established that c-Src and EGFR phosphorylate each other in a positive feedback loop 25,26. Our previous study showed that c-Src activation mediated cetuximab resistance in colon cancer cells,14 which have not been confirmed in GC yet. Moreover, our study showed that c-Src was activated by RANKL in the migration of breast cancer cells 13.…”

Section: Discussionmentioning

confidence: 92%

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RANKL/RANK pathway abrogates cetuximab sensitivity in gastric cancer cells via activation of EGFR and c-Src

Zhang¹,

Song²,

Song³

et al. 2017

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Overexpression of EGFR is commonly seen in gastric cancer (GC). However, patients with GC show resistance to anti-EGFR treatments. RAS mutations are rare in GC and cannot explain de novo resistance to EGFR treatments. Therefore, it is particularly important to explore the mechanisms of resistance to anti-EGFR treatments. The RANKL activates the EGFR pathway in osteoclasts, and the RANK is expressed in gastric carcinoma. Whether the RANKL/RANK pathway has an effect on the EGFR pathway in GC remains unknown. Expressions of EGFR and RANK in GC tissues were detected using immunohistochemical staining. Nineteen patients (28%) showed high-level RANKL expression, and 33 patients (48%) showed high-level RANK expression. There was a positive correlation between expression of EGFR and RANK (P<0.001). In an in vitro study, RANKL induced activation of the EGFR pathway and further abrogated cetuximab sensitivity in GC cells. Knockdown of RANK or use of the RANKL inhibitor enhanced cetuximab effect by decreasing RANKL-induced EGFR activation. Furthermore, we showed that c-SRC mediated the EGFR activation induced by the RANKL/RANK pathway and that c-SRC inhibitor reversed the suppression of RANKL on the effect of cetuximab. In conclusion, our results suggest that in GC cells, the RANKL/RANK pathway activates the EGFR pathway and thereby causes resistance to anti-EGFR treatments.

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Section: Discussionmentioning

confidence: 92%

“…Western blot was performed as previously described 14. The following antibodies were used: Anti-RANK antibody was obtained from Bethyl Laboratories, Inc. (Montgomery, TX, USA).…”

Section: Methodsmentioning

confidence: 99%

RANKL/RANK pathway abrogates cetuximab sensitivity in gastric cancer cells via activation of EGFR and c-Src

Zhang¹,

Song²,

Song³

et al. 2017

OTT

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“…HGF is the ligand for the MET receptor and can activate many of the same signaling pathways as EGFR. Furthermore, dysregulated MET signaling has been linked to HNSCC [41] and is a known mechanism of resistance to EGFR inhibitors [12,42]. Baseline serum IL6 levels were highly correlated with baseline HGF levels, suggesting a potential interaction between the IL6 pathway and the HGF/MET pathway in HNSCC.…”

Section: Discussionmentioning

confidence: 99%

IL6 is associated with response to dasatinib and cetuximab: Phase II clinical trial with mechanistic correlatives in cetuximab-resistant head and neck cancer

et al. 2017

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Objective Src family kinase (SFK) activation circumvents epidermal growth factor receptor (EGFR) targeting in head and neck squamous cell carcinoma (HNSCC); dual SFK-EGFR targeting could overcome cetuximab resistance. Patients and methods We conducted a Simon two-stage, phase II trial of the SFK inhibitor, dasatinib, and cetuximab in biomarker-unselected patients with cetuximab-resistant, recurrent/metastatic HNSCC. Pre- and post-treatment serum levels of interleukin-6 (IL6) were measured by ELISA. HNSCC cell lines were assessed for viability and effects of IL6 modulation following dasatinib-cetuximab treatment. Results In the first stage, 13 patients were evaluable for response: 7 had progressive and 6 had stable disease (SD). Enrollment was halted for futility, and biomarker analysis initiated. Low serum IL6 levels were associated with SD (raw p = 0.028, adjusted p = 0.14) and improved overall survival (p = 0.010). The IL6 classifier was validated in a separate trial of the same combination, but was unable to segregate survival risk in a clinical trial of cetuximab and bevacizumab suggesting serum IL6 may be specific for the dasatinib-cetuximab combination. Enhanced in vitro HNSCC cell death was observed with dasatinib-cetuximab versus single agent treatment; addition of IL6-containing media abrogated this effect. Conclusion Clinical benefit and overall survival from the dasatinib-cetuximab combination were improved among patients with low serum IL6. Preclinical studies support IL6 as a modifier of dasatinib-cetuximab response. In the setting of clinical cetuximab resistance, serum IL6 is a candidate predictive marker specific for combined dasatinib-cetuximab. The trial was modified and redesigned as a biomarker-enriched Phase II study enrolling patients with undetectable IL6.

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“…Recent evidence indicates the MET signaling pathway may play an important role in CRC growth and metastasis, 26,32,33 is associated with more advanced metastatic disease and tumor stage, 34,35 and may mediate resistance to EGFR inhibitors. 36,37 Dual MET and EGFR blockade could potentially provide more durable clinical benefit in mCRC, which led to the investigation of new MET-targeting agents, including tivantinib. Preclinical findings suggest that tivantinib may also affect the cytoskeleton, and recent studies show this may happen via MET and paxillin inhibition.…”

Section: Discussionmentioning

confidence: 99%

A randomized, placebo‐controlled, phase 1/2 study of tivantinib (ARQ 197) in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with wild‐type KRAS who have received first‐line systemic therapy

Eng

Bessudo

Hart

et al. 2016

Intl Journal of Cancer

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Cetuximab in combination with an irinotecan‐containing regimen is a standard treatment in patients with KRAS wild‐type (KRAS WT), metastatic colorectal cancer (mCRC). We investigated the addition of the oral MET inhibitor tivantinib to cetuximab + irinotecan (CETIRI) based on preclinical evidence that activation of the MET pathway may confer resistance to anti‐EGFR therapy. Previously treated patients with KRAS WT advanced or mCRC were enrolled. The phase 1, open‐label 3 + 3, dose‐escalation study evaluated the safety and maximally tolerated dose of tivantinib plus CETIRI. The phase 2, randomized, double‐blinded, placebo‐controlled study of biweekly CETIRI plus tivantinib or placebo was restricted to patients who had received only one prior line of chemotherapy. The phase 2 primary endpoint was progression‐free survival (PFS). The recommended phase 2 dose was tivantinib (360 mg/m2 twice daily) with biweekly cetuximab (500 mg/m2) and irinotecan (180 mg/m2). Among 117 patients evaluable for phase 2 analysis, no statistically significant PFS difference was observed: 8.3 months on tivantinib vs. 7.3 months on placebo (HR, 0.85; 95% confidence interval, 0.55–1.33; P = 0.38). Subgroup analyses trended in favor of tivantinib in patients with MET‐High tumors by immunohistochemistry, PTEN‐Low tumors, or those pretreated with oxaliplatin, but subgroups were too small to draw conclusions. Neutropenia, diarrhea, nausea and rash were the most frequent severe adverse events in tivantinib‐treated patients. The combination of tivantinib and CETIRI was well tolerated but did not significantly improve PFS in previously treated KRAS WT mCRC. Tivantinib may be more active in specific subgroups.

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Cetuximab-Induced MET Activation Acts as a Novel Resistance Mechanism in Colon Cancer Cells

Cited by 34 publications

References 26 publications

RANKL/RANK pathway abrogates cetuximab sensitivity in gastric cancer cells via activation of EGFR and c-Src

RANKL/RANK pathway abrogates cetuximab sensitivity in gastric cancer cells via activation of EGFR and c-Src

IL6 is associated with response to dasatinib and cetuximab: Phase II clinical trial with mechanistic correlatives in cetuximab-resistant head and neck cancer

A randomized, placebo‐controlled, phase 1/2 study of tivantinib (ARQ 197) in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with wild‐type KRAS who have received first‐line systemic therapy

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