Inhibition of BMP signaling overcomes acquired resistance to cetuximab in oral squamous cell carcinomas

Yin, Jinlong,Jung, Ji-Eun,Choi, Sun Il,Kim, Sung Soo,Oh, Young Taek,Kim, Tae-Hoon,Choi, Eunji,Lee, Sun Joo,Kim, Hana,Kim, Eun Ok,Lee, Yu Sun,Chang, Hee Jin,Park, Joo Yong,Kim, Yeejeong,Yun, Tak,Heo, K Elsevier 2018 Cancer letters Vol.414 No.-

<P><B>Abstract</B></P> <P>Despite expressing high levels of the epidermal growth factor receptor (EGFR), a majority of oral squamous cell carcinoma (OSCC) patients show limited response to cetuximab and ultimately develop drug resistance. However, mechanism underlying cetuximab resistance in OSCC is not clearly understood. Here, using a mouse orthotopic xenograft model of OSCC, we show that bone morphogenic protein-7-phosphorylated Smad-1, -5, -8 (BMP7-p-Smad1/5/8) signaling contributes to cetuximab resistance. Tumor cells isolated from the recurrent cetuximab-resistant xenograft models exhibited low EGFR expression but extremely high levels of p-Smad1/5/8. Treatment with the bone morphogenic protein receptor type 1 (BMPRI) inhibitor, DMH1 significantly reduced cetuximab-resistant OSCC tumor growth, and combined treatment of DMH1 and cetuximab remarkably reduced relapsed tumor growth <I>in vivo</I>. Importantly, p-Smad1/5/8 level was elevated in cetuximab-resistant patients and this correlated with poor prognosis. Collectively, our results indicate that the BMP7-p-Smad1/5/8 signaling is a key pathway to acquired cetuximab resistance, and demonstrate that combination therapy of cetuximab and a BMP signaling inhibitor as potentially a new therapeutic strategy for overcoming acquired resistance to cetuximab in OSCC.</P> <P><B>Highlights</B></P> <P> <UL> <LI> BMP7-p-Smad1/5/8 signaling contributes to cetuximab resistance in OSCC. </LI> <LI> DMHI, a BMP signaling inhibitor, reduced cetuximab-resistant OSCC tumor growth. </LI> <LI> Combined treatment of DMH1 and cetuximab significantly reduced relapsed tumor growth <I>in vivo.</I> </LI> <LI> p-Smad1/5/8 overexpression in OSCC patients was associated with poor disease free survival. </LI> </UL> </P>

Irinotecan을 포함한 선행치료를 받은 전이 및 재발 대장암에서 Cetuximab과 FOLFIRI 병합치료 효과의 후향적 분석

박재우,문선미,황대용 대한대장항문학회 2008 Annals of Coloproctolgy Vol.24 No.5

Purpose: Many reports about efficacy of cetuximab in the prolongation of survival have been published. Especially, the combination of cetuximab and FOLFIRI has a high activity even in prior irinotecan refractory metastatic colorectal cancer (mCRC). Beside small number of patients, we are trying to evaluate the efficacy and safety of cetuximab combined with FOLFIRI for patients who prior irinotecan chemotherapy had failed. Methods: A retrospective analysis of 26 patients treated with cetuximab with FOLFIRI from July 2006 to August 2007 was done. All patients had already been treated with FOLFIRI chemotherapy in 1st line or 2nd line regimens for mCRC. The initial dose of cetuximab was 400 mg/m2 at the 1st week, after which the dose was 250 mg/m2 weekly plus FOLFIRI biweekly. We defined 1 cycle as 8 weeks, and the responses were evaluated at week 8. Results: The median follow-up period was 6.2 (1.1∼13.9) months. After 8 weeks, 50% of the patients had a partial response, and the disease control rate was 57.5%. The median time to progression was 3 months. EGFR expression and tumor response had no correlation (P=0.07). Skin reaction and tumor response (median time to progression) had a significant correlation (P= 0.022). Cetuximab did not increase the toxicity associated with FOLFIRI, except for an acneiform rash. Conclusions: Cetuximab combined with FOLFIRI chemotherapy was effective in treating mCRC patients after FOLFIRI regimen chemotherapy.

The effect of near-infrared fluorescence conjugation on the anti-cancer potential of cetuximab

Ji Young Yun,Byung-Hwa Hyun,Sang Yoon Nam,Young Won Yun,Hu-Jang Lee,Beom-Jun Lee 한국실험동물학회 2018 Laboratory Animal Research Vol.34 No.1

This study investigated the anti-cancer potential of a near-infrared fluorescence (NIRF) molecule conjugated with Cetuximab (Cetuximab-NIRF) in six-week-old female BALB/c athymic (nu+/nu+) nude mice. A431 cells were cultured and injected into the animals to induce solid tumors. Paclitaxel (30 mg/kg body weight (BW)), Cetuximab (1 mg/kg BW), and Cetuximab-NIRF (0.25, 0.5 and 1.0 mg/kg BW) were intraperitoneally injected twice a week into the A431 cell xenografts of the nude mice. Changes in BW, tumor volume and weight, fat and lean mass, and diameter of the peri-tumoral blood vessel were determined after two weeks. Tumor volumes and weights were significantly decreased in the Cetuximab-NIRF (1 mg/kg BW) group compared with the control group (P<0.001). Lean mass and total body water content were also conspicuously reduced in the Cetuximab-NIRF (1 mg/kg BW) group compared with the vehicle control group. Peri-tumoral blood vessel diameters were very thin in the Cetuximab-NIRF groups compared with those of the paclitaxel group. These results indicate that the conjugation of Cetuximab with NIRF does not affect the anti-cancer potential of Cetuximab and NIRF can be used for molecular imaging in cancer treatments.

점진적 단계 단축을 적용한 cetuximab 탈감작요법 사례 1예

서장호,정지웅,윤정은,김현화,김현지,이서영,강혜련 대한 소아알레르기 호흡기학회 2022 Allergy Asthma & Respiratory Disease Vol.10 No.3

Desensitization therapy can help overcome severe hypersensitivity reactions and allow continuing administration of the culprit agents. However, this is time- and labor-intensive due to a prolonged infusion time and the serial adjustment of infusion rate between steps. Therefore, simplified protocols using fewer steps have been tested, although currently there is no established standard strategy. Cetuximab plays an important role in the treatment of metastatic colorectal cancer. Although cetuximab is well tolerated, severe infusion reactions occur in 1.1% of patients, and most occur within 1 hour of receiving the first dose. Here, we report a recent attempt to shorten the steps of gradual cetuximab desensitization. A 57-year-old male patient diagnosed with obstructive sigmoid colon cancer received cetuximab chemotherapy and experienced immediate anaphylaxis at the first cycle. A one-bag, 17-step desensitization protocol was applied to cetuximab administration. After the first successful desensitization cycle, the process of desensitization was shortened 1–2 step(s) per cycle, down to 2 steps, without a breakthrough reaction. The patient ultimately received regular infusions. Shortening of the rapid desensitization protocol can be considered if the previous cycle is well-tolerated, even in a patient who suffered previous anaphylaxis to cetuximab.

전이성 직결장암 환자에서 원발병소 위치에 따른 Cetuximab과 Bevacizumab의 치료효과 비교 분석

김유진,안혜림,권은영 한국병원약사회 2021 病院藥師會誌 Vol.38 No.1

Background : Recent reports on metastatic colorectal cancer (mCRC) demonstrated that the primary tumor origin site was related to significantly different effects of biologic therapy (BT). However, in the Korean clinical field, patients are still prescribed cetuximab regardless of the primary tumor site. Therefore, it is necessary to determine whether there is a different response to BT in Korean patients as well. This study analyzed the correlation between the effect of BT and the primary tumor origin in patients with mCRC. Methods : This study included all patients diagnosed with mCRC from January 1, 2015, through December 31, 2016, who were treated with first-line chemotherapy containing bevacizumab or cetuximab. We followed the patients using EMR analysis until September 30, 2018. We compared the different effects of BT based on the primary tumor site by the time to progression (TTP) and the overall response rate (ORR). Results : One hundred and sixty-one patients were eligible for the study, 50 patients had right-sided primary tumor origins and 111 patients had tumors on the left. Among patients who received bevacizumab, there was no significant difference regardless of the primary tumor site, whereas, in patients treated with cetuximab, left-sided mCRC was related to longer TTP compared to right-sided (hazard ratio [HR]=1.92, 95% CI: 0.98 – 3.60; p=0.050). In other words, there was no significant difference between bevacizumab and cetuximab in the left-sided mCRC patients. However, in the right-sided mCRC patients, bevacizumab showed a significantly improved TTP compared to cetuximab (HR=2.08, 95% CI: 1.03 – 4.03; p=0.036). Conclusion : The primary tumor site was related to the response to BT in patients with mCRC. Right-sided primary tumor origin was associated with significantly improved TTP when treated with bevacizumab compared to cetuximab. Therefore, we recommend considering not only the molecular status but the primary tumor site when choosing BT for mCRC patients in the future.

구강 편평상피세포암 마우스 모델에서 상피성장인자 수용체 억제제를 적용한 분자표적치료

박영욱,Park, Young-Wook 대한악안면성형재건외과학회 2009 Maxillofacial Plastic Reconstructive Surgery Vol.31 No.1

Purpose: We determined the therapeutic effect of an epidermal growth factor receptor (EGFR)-specific monoclonal antibody (mAb), cetuximab (Erbitux) on the growth of oral squamous cell carcinoma (OSCC) xenografted in athymic nude mice. Experimental Design: We induced subcutaneous tumors by inoculating human tumor cell suspension into the right flank of nude mice. Nude mice with subcutaneous tumors were randomized to receive cetuximab alone, paclitaxel alone, cetuximab plus paclitaxel, or a placebo (control). Antitumor mechanisms of cetuximab were determined by immunohistochemical and apoptosis assays. Results: Cetuximab, paclitaxel, and cetuximab/paclitaxel combined therapy resulted in 50%, 52%, 67% in vivo inhibition of tumor proliferation, respectively. Tumors of mice treated with cetuximab plus paclitaxel demonstrated decreased PCNA-positive tumor cells and increased apoptotic tumor cells, which slowed growth of the murine tumors. Conclusion: These data show that EGFR can be a molecular target for the treatment of OSCC. And combination therapy with cetuximab and paclitaxel warrants further clinical study.

Identifying the Patterns of Adverse Drug Responses of Cetuximab

박지현 한국임상약학회 2022 한국임상약학회지 Vol.32 No.3

Background: Monoclonal antibodies for the treatment of patients with different types of cancer, such as cetuximab, have been widelyused for the past 10 years in oncology. Although drug information package insert contains some representative adverse events whichwere observed in the clinical trials for drug approval, the overall adverse event patterns on the real-world cetuximab use were lessinvestigated. Also, there have been no published papers that deal with the full spectrums of adverse drug events of cetuximab usingnational-wide drug safety surveillance systems. Methods: In this study, we detected new adverse event signals of cetuximab in theKorea Adverse Event Reporting System (KAERS) by utilizing proportional reporting ratios, reporting odds ratios, and informationcomponents indices. Results: The KAERS database included 869,819 spontaneous adverse event reports, among which 2,116reports contained cetuximab. We compared the labels of cetuximab among the United States, European Union, Australia, Japan, andKorea to compare the current labeling information and newly detected signals of our study. Some of the signals includinghyperkeratosis, tenesmus, folliculitis, esophagitis, neuralgia, disseminated intravascular coagulopathy, and skin/throat tightnesswere not labeled in the five countries. Conclusion: We identified new signals that were not known at the time of market approval.

Cetuximab에 의한 아나필락시스를 보인 환자에서 성공적인 탈감작 적용 1예

원하경 ( Ha Kyeong Won ),문성도 ( Sung Do Moon ),심지수 ( Ji Su Shim ),정수지 ( Soo Jie Chung ),김건우 ( Gun Woo Kim ),김수정 ( Su Jeong Kim ),박한기 ( Han Ki Park ),강혜련 ( Hye Ryun Kang ) 대한천식알레르기학회 2015 Allergy Asthma & Respiratory Disease Vol.3 No.4

Cetuximab, a chimeric mouse-human immunoglobulin, is an antiepidermal growth factor receptor monoclonal antibody. It has been approved by the U.S. Food and Drug Administration for the treatment of metastatic colorectal and head/neck cancer, but can cause fatal hypersensitivity reactions in some patients. A 66-year-old male with metastatic sigmoid cancer had cetuximab-induced anaphylaxis when the first dose of cetuximab was administered. Cetuximab was safely readministered for another 15 cycles based on the rapid desensitization protocol. We experienced a case of cetuximab-induced anaphylaxis on the first exposure which was successfully managed by rapid desensitization. (Allergy Asthma Respir Dis 2015;3:294-296)

<i>Phellinus linteus</i> Grown on Germinated Brown Rice Increases Cetuximab Sensitivity of KRAS-Mutated Colon Cancer

Park, Hye-Jin,Park, Jeong-Bin,Lee, Sang-Jae,Song, Minjung MDPI AG 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.8

<P>Colon cancer is one of the most common types of cancer, and it has recently become a leading cause of death worldwide. Among colon cancers, the v-ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated form is notorious for its non-druggable features. Cetuximab, a monoclonal antibody that binds to the epidermal growth factor receptor, has been introduced as an antitumor therapy; however, secondary resistance and side effects significantly limit its effective use in these cancers. In this study, we prepared <I>Phellinuslinteus</I> on germinated brown rice (PBR) extracts to increase the sensitivity of KRAS-mutated colon cancers to cetuximab. The combined treatment of PBR extract and cetuximab suppressed SW480 cell viability/proliferation, with the cells exhibiting altered cellular morphology and clonogenic potential. AnnexinV–fluorescein isothiocyanate/propidium iodide–stained flow cytometry and Western blotting were performed, and PBR extract combined with cetuximab treatment increased apoptosis of the SW480 cells and suppressed their KRAS protein expression. The potential of PBR as a synergistic anticancer agent was further investigated in a tumor-xenografted mouse model. Tumor growth was significantly suppressed with PBR extract and cetuximab co-treatment. In conclusion, PBR increased the sensitivity of KRAS-mutated colon cancer cells to cetuximab, which indicates the potential use of PBR as a medical food against colon cancer.</P>

Topical recombinant human epidermal growth factor for cetuximab-induced paronychia

( Ji Young Choi ),( Seong Jin Jo ),( Jung-im Na ) 대한피부과학회 2018 대한피부과학회 학술발표대회집 Vol.70 No.1

Cetuximab, a chimeric human-murine monoclonal antibody against epidermal growth factor receptor (EGFR), has been widely utilized for multiple malignancies. Though the incidence of EGFR-inhibitor-induced paronychia is up to 10-15%, treatments of EGFR-inhibitor induced paronychia are limited to relieving symptoms or preventing secondary infection. Here, we report a case of cetuximab-induced paronychia which has shown significant improvement after treatment with topical recombinant human epidermal growth factor (rhEGF) ointment. A 56-year-old male treated with biweekly FOLFIRI-Cetuximab for sigmoid cancer developed multiple paronychia with periungual granulation on his toenails and fingernails 3 months after the initiation of chemotherapy. After a month without further treatment, paronychia aggravated and the patient began to use topical rhEGF ointment. After treating 7 weeks with topical rhEGF, paronychia showed significant improvement with minimal to no pain or discharge. Unlike other conservative treatment options, topical rhEGF affects wound-healing mechanisms by promoting re-epithelialization, granulation and angiogenesis. Our case of successful treatment of cetuximab-induced paronychia with rhEGF highlights the therapeutic potential of rhEGF, a potent stimulator of epithelial and endothelial cells and fibroblast proliferation, to promote tissue repair and suggests further application of rhEGF.