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 Park; Sung Weon Choi

doi:10.1016/j.canlet.2017.11.013

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

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21 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 language	English
Pages (from-to)	181-189
Number of pages	9
Journal	Cancer letters
Volume	414
DOIs	https://doi.org/10.1016/j.canlet.2017.11.013
Publication status	Published - 2018 Feb 1

Bibliographical note

Funding Information:
This research was supported by grants from the National Cancer Center, Republic of Korea ( NCC-1210480 , NCC-1510610 , NCC-1510061 , NCC-1510202 , NCC-1630980 , and NCC-1710400 ), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT ( NRF-2015R1C1A1A01054963 and NRF-2017R1A2B4011741 ), and the Korea Research Fellowship Program through the National Research Foundation of Korea (KRF) funded by Ministry of Science and ICT ( NRF-2015H1D3A1036090 ).

Publisher Copyright:
© 2017 Elsevier B.V.

Keywords

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

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.canlet.2017.11.013

Cite this

Yin, J., Jung, J. E., Choi, S. I., Kim, S. S., Oh, Y. T., Kim, T. H., Choi, E., Lee, S. J., Kim, H., Kim, E. O., Lee, Y. S., Chang, H. J., Park, J. Y., Kim, Y., Yun, T., Heo, K., Kim, Y. J., Kim, H., Kim, Y. 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

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

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title = "Inhibition of BMP signaling overcomes acquired resistance to cetuximab in oral squamous cell carcinomas",

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.",

keywords = "BMP7, Cetuximab, DMH1, OSCC, Resistance, p-Smad1/5/8",

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

note = "Funding Information: This research was supported by grants from the National Cancer Center, Republic of Korea ( NCC-1210480 , NCC-1510610 , NCC-1510061 , NCC-1510202 , NCC-1630980 , and NCC-1710400 ), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT ( NRF-2015R1C1A1A01054963 and NRF-2017R1A2B4011741 ), and the Korea Research Fellowship Program through the National Research Foundation of Korea (KRF) funded by Ministry of Science and ICT ( NRF-2015H1D3A1036090 ). Publisher Copyright: {\textcopyright} 2017 Elsevier B.V.",

year = "2018",

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doi = "10.1016/j.canlet.2017.11.013",

language = "English",

volume = "414",

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T1 - Inhibition of BMP signaling overcomes acquired resistance to cetuximab in oral squamous cell carcinomas

AU - Yin, Jinlong

AU - Jung, Ji Eun

AU - Choi, Sun Il

AU - Kim, Sung Soo

AU - Oh, Young Taek

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

AU - Heo, Kyun

AU - Kim, Youn Jae

AU - Kim, Hyunggee

AU - Kim, Yun Hee

AU - Park, Jong Bae

AU - Choi, Sung Weon

N1 - Funding Information: This research was supported by grants from the National Cancer Center, Republic of Korea ( NCC-1210480 , NCC-1510610 , NCC-1510061 , NCC-1510202 , NCC-1630980 , and NCC-1710400 ), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT ( NRF-2015R1C1A1A01054963 and NRF-2017R1A2B4011741 ), and the Korea Research Fellowship Program through the National Research Foundation of Korea (KRF) funded by Ministry of Science and ICT ( NRF-2015H1D3A1036090 ). Publisher Copyright: © 2017 Elsevier B.V.

PY - 2018/2/1

Y1 - 2018/2/1

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.

AB - 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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KW - Cetuximab

KW - DMH1

KW - OSCC

KW - Resistance

KW - p-Smad1/5/8

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DO - 10.1016/j.canlet.2017.11.013

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JO - Cancer letters

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ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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