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

Jinlong Yin, Ji Eun Jung, Sun Il Choi, Sung Soo Kim, Young Taek Oh, Tae Hoon Kim, Eunji Choi, Sun Joo Lee, Hana Kim, Eun Ok Kim, Yu Sun Lee, Hee Jin Chang, Joo Yong Park, Yeejeong Kim, Tak Yun, Kyun Heo, Youn Jae Kim, Hyunggee Kim, Yun Hee Kim, Jong Bae ParkSung Weon Choi

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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 in vivo. 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.

Original languageEnglish
Pages (from-to)181-189
Number of pages9
JournalCancer Letters
Volume414
DOIs
Publication statusPublished - 2018 Feb 1

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Squamous Cell Carcinoma
Epidermal Growth Factor Receptor
Heterografts
Cetuximab
Bone and Bones
Neoplasms
Therapeutics
Growth
Drug Resistance
Proteins

Keywords

  • BMP7
  • Cetuximab
  • DMH1
  • OSCC
  • p-Smad1/5/8
  • Resistance

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Yin, J., Jung, J. E., Choi, S. I., Kim, S. S., Oh, Y. T., Kim, T. H., ... Choi, S. W. (2018). Inhibition of BMP signaling overcomes acquired resistance to cetuximab in oral squamous cell carcinomas. Cancer Letters, 414, 181-189. https://doi.org/10.1016/j.canlet.2017.11.013

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, Kyun; Kim, Youn Jae; Kim, Hyunggee; Kim, Yun Hee; Park, Jong Bae; Choi, Sung Weon.

In: Cancer Letters, Vol. 414, 01.02.2018, p. 181-189.

Research output: Contribution to journalArticle

Yin, J, Jung, JE, Choi, SI, Kim, SS, Oh, YT, Kim, TH, Choi, E, Lee, SJ, Kim, H, Kim, EO, Lee, YS, Chang, HJ, Park, JY, Kim, Y, Yun, T, Heo, K, Kim, YJ, Kim, H, Kim, YH, Park, JB & Choi, SW 2018, 'Inhibition of BMP signaling overcomes acquired resistance to cetuximab in oral squamous cell carcinomas', Cancer Letters, vol. 414, pp. 181-189. https://doi.org/10.1016/j.canlet.2017.11.013
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, Kyun ; Kim, Youn Jae ; Kim, Hyunggee ; Kim, Yun Hee ; Park, Jong Bae ; Choi, Sung Weon. / Inhibition of BMP signaling overcomes acquired resistance to cetuximab in oral squamous cell carcinomas. In: Cancer Letters. 2018 ; Vol. 414. pp. 181-189.
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abstract = "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 in vivo. 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.",
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AU - Kim, Tae Hoon

AU - Choi, Eunji

AU - Lee, Sun Joo

AU - Kim, Hana

AU - Kim, Eun Ok

AU - Lee, Yu Sun

AU - Chang, Hee Jin

AU - Park, Joo Yong

AU - Kim, Yeejeong

AU - Yun, Tak

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AU - Choi, Sung Weon

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N2 - 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 in vivo. 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.

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