MITF Modulates Therapeutic Resistance through EGFR Signaling.

Research output: Contribution to journalArticle

Standard

MITF Modulates Therapeutic Resistance through EGFR Signaling. / Ji, Zhenyu; Erin Chen, Yiyin; Kumar, Raj; Taylor, Michael; Jenny Njauw, Ching-Ni; Miao, Benchun; Frederick, Dennie T; Wargo, Jennifer A; Flaherty, Keith T; Jönsson, Göran B; Tsao, Hensin.

In: Journal of Investigative Dermatology, Vol. 135, No. 7, 2015, p. 1863-1872.

Research output: Contribution to journalArticle

Harvard

Ji, Z, Erin Chen, Y, Kumar, R, Taylor, M, Jenny Njauw, C-N, Miao, B, Frederick, DT, Wargo, JA, Flaherty, KT, Jönsson, GB & Tsao, H 2015, 'MITF Modulates Therapeutic Resistance through EGFR Signaling.', Journal of Investigative Dermatology, vol. 135, no. 7, pp. 1863-1872. https://doi.org/10.1038/jid.2015.105

APA

Ji, Z., Erin Chen, Y., Kumar, R., Taylor, M., Jenny Njauw, C-N., Miao, B., ... Tsao, H. (2015). MITF Modulates Therapeutic Resistance through EGFR Signaling. Journal of Investigative Dermatology, 135(7), 1863-1872. https://doi.org/10.1038/jid.2015.105

CBE

Ji Z, Erin Chen Y, Kumar R, Taylor M, Jenny Njauw C-N, Miao B, Frederick DT, Wargo JA, Flaherty KT, Jönsson GB, Tsao H. 2015. MITF Modulates Therapeutic Resistance through EGFR Signaling. Journal of Investigative Dermatology. 135(7):1863-1872. https://doi.org/10.1038/jid.2015.105

MLA

Vancouver

Ji Z, Erin Chen Y, Kumar R, Taylor M, Jenny Njauw C-N, Miao B et al. MITF Modulates Therapeutic Resistance through EGFR Signaling. Journal of Investigative Dermatology. 2015;135(7):1863-1872. https://doi.org/10.1038/jid.2015.105

Author

Ji, Zhenyu ; Erin Chen, Yiyin ; Kumar, Raj ; Taylor, Michael ; Jenny Njauw, Ching-Ni ; Miao, Benchun ; Frederick, Dennie T ; Wargo, Jennifer A ; Flaherty, Keith T ; Jönsson, Göran B ; Tsao, Hensin. / MITF Modulates Therapeutic Resistance through EGFR Signaling. In: Journal of Investigative Dermatology. 2015 ; Vol. 135, No. 7. pp. 1863-1872.

RIS

TY - JOUR

T1 - MITF Modulates Therapeutic Resistance through EGFR Signaling.

AU - Ji, Zhenyu

AU - Erin Chen, Yiyin

AU - Kumar, Raj

AU - Taylor, Michael

AU - Jenny Njauw, Ching-Ni

AU - Miao, Benchun

AU - Frederick, Dennie T

AU - Wargo, Jennifer A

AU - Flaherty, Keith T

AU - Jönsson, Göran B

AU - Tsao, Hensin

PY - 2015

Y1 - 2015

N2 - Response to targeted therapies varies significantly despite shared oncogenic mutations. Nowhere is this more apparent than in BRAF(V600E)-mutated melanomas where initial drug response can be striking and yet relapse is commonplace. Resistance to BRAF inhibitors have been attributed to the activation of various receptor tyrosine kinases (RTKs) though the underlying mechanisms have been largely uncharacterized. Here, we found that EGFR induced vemurafenib resistance is ligand dependent. We then employed whole-genome expression analysis and discovererd that vemurafenib resistance correlated with the loss of MITF, along with its melanocyte lineage program, and with the activation of EGFR signaling. An inverse relationship between MITF, vemurafenib resistance and EGFR was then observed in patient samples of recurrent melanoma and was conserved across melanoma cell lines and patients' tumor specimens. Functional studies revealed that MITF depletion activated EGFR signaling and consequently recapitulated the resistance phenotype. In contrast, forced expression of MITF in melanoma and colon cancer cells inhibited EGFR and conferred sensitivity to BRAF/MEK inhibitors. These findings indicate that an "autocrine drug resistance loop" is suppressed by melanocyte lineage signal(s), such as MITF. This resistance loop modulates drug response and could explain the unique sensitivity of melanomas to BRAF inhibition.Journal of Investigative Dermatology accepted article preview online, 19 March 2015. doi:10.1038/jid.2015.105.

AB - Response to targeted therapies varies significantly despite shared oncogenic mutations. Nowhere is this more apparent than in BRAF(V600E)-mutated melanomas where initial drug response can be striking and yet relapse is commonplace. Resistance to BRAF inhibitors have been attributed to the activation of various receptor tyrosine kinases (RTKs) though the underlying mechanisms have been largely uncharacterized. Here, we found that EGFR induced vemurafenib resistance is ligand dependent. We then employed whole-genome expression analysis and discovererd that vemurafenib resistance correlated with the loss of MITF, along with its melanocyte lineage program, and with the activation of EGFR signaling. An inverse relationship between MITF, vemurafenib resistance and EGFR was then observed in patient samples of recurrent melanoma and was conserved across melanoma cell lines and patients' tumor specimens. Functional studies revealed that MITF depletion activated EGFR signaling and consequently recapitulated the resistance phenotype. In contrast, forced expression of MITF in melanoma and colon cancer cells inhibited EGFR and conferred sensitivity to BRAF/MEK inhibitors. These findings indicate that an "autocrine drug resistance loop" is suppressed by melanocyte lineage signal(s), such as MITF. This resistance loop modulates drug response and could explain the unique sensitivity of melanomas to BRAF inhibition.Journal of Investigative Dermatology accepted article preview online, 19 March 2015. doi:10.1038/jid.2015.105.

U2 - 10.1038/jid.2015.105

DO - 10.1038/jid.2015.105

M3 - Article

VL - 135

SP - 1863

EP - 1872

JO - Advances in biology of skin

T2 - Advances in biology of skin

JF - Advances in biology of skin

SN - 1523-1747

IS - 7

ER -