Orthogonal targeting of EGFRvIII expressing glioblastomas through simultaneous EGFR and PLK1 inhibition

Ying Shen; Jie Li; Masayuki Nitta; Diahnn Futalan; Tyler Steed; Jeffrey M. Treiber; Zack Taich; Deanna Stevens; Jill Wykosky; Hong Zhuan Chen; Bob S. Carter; Oren J. Becher; Richard Kennedy; Fumiko Esashi; Jann N. Sarkaria; Frank B. Furnari; Webster K. Cavenee; Arshad Desai; Clark C. Chen

doi:10.18632/oncotarget.3996

Orthogonal targeting of EGFRvIII expressing glioblastomas through simultaneous EGFR and PLK1 inhibition

Ying Shen, Jie Li, Masayuki Nitta, Diahnn Futalan, Tyler Steed, Jeffrey M. Treiber, Zack Taich, Deanna Stevens, Jill Wykosky, Hong Zhuan Chen, Bob S. Carter, Oren J. Becher, Richard Kennedy, Fumiko Esashi, Jann N. Sarkaria, Frank B. Furnari, Webster K. Cavenee, Arshad Desai, Clark C. Chen

Radiation Oncology

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

We identified a synthetic lethality between PLK1 silencing and the expression of an oncogenic Epidermal Growth Factor Receptor, EGFRvIII. PLK1 promoted homologous recombination (HR), mitigating EGFRvIII induced oncogenic stress resulting from DNA damage accumulation. Accordingly, PLK1 inhibition enhanced the cytotoxic effects of the DNA damaging agent, temozolomide (TMZ). This effect was significantly more pronounced in an Ink4a/Arf(-/-) EGFRvIII glioblastoma model relative to an Ink4a/ Arf(-/-) PDGF-β model. The tumoricidal and TMZ-sensitizing effects of BI2536 were uniformly observed across Ink4a/Arf(-/-) EGFRvIII glioblastoma clones that acquired independent resistance mechanisms to EGFR inhibitors, suggesting these resistant clones retain oncogenic stress that required PLK1 compensation. Although BI2536 significantly augmented the anti-neoplastic effect of EGFR inhibitors in the Ink4a/ Arf(-/-) EGFRvIII model, durable response was not achieved until TMZ was added. Our results suggest that optimal therapeutic effect against glioblastomas requires a "multi-orthogonal" combination tailored to the molecular physiology associated with the target cancer genome.

Original language	English (US)
Pages (from-to)	11751-11767
Number of pages	17
Journal	Oncotarget
Volume	6
Issue number	14
DOIs	https://doi.org/10.18632/oncotarget.3996
State	Published - 2015

Keywords

EGFR
EGFRvIII
Glioblastoma
Synthetic lethality

ASJC Scopus subject areas

Oncology

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Shen, Y., Li, J., Nitta, M., Futalan, D., Steed, T., Treiber, J. M., Taich, Z., Stevens, D., Wykosky, J., Chen, H. Z., Carter, B. S., Becher, O. J., Kennedy, R., Esashi, F., Sarkaria, J. N., Furnari, F. B., Cavenee, W. K., Desai, A., & Chen, C. C. (2015). Orthogonal targeting of EGFRvIII expressing glioblastomas through simultaneous EGFR and PLK1 inhibition. Oncotarget, 6(14), 11751-11767. https://doi.org/10.18632/oncotarget.3996

Shen, Y, Li, J, Nitta, M, Futalan, D, Steed, T, Treiber, JM, Taich, Z, Stevens, D, Wykosky, J, Chen, HZ, Carter, BS, Becher, OJ, Kennedy, R, Esashi, F, Sarkaria, JN, Furnari, FB, Cavenee, WK, Desai, A & Chen, CC 2015, 'Orthogonal targeting of EGFRvIII expressing glioblastomas through simultaneous EGFR and PLK1 inhibition', Oncotarget, vol. 6, no. 14, pp. 11751-11767. https://doi.org/10.18632/oncotarget.3996

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abstract = "We identified a synthetic lethality between PLK1 silencing and the expression of an oncogenic Epidermal Growth Factor Receptor, EGFRvIII. PLK1 promoted homologous recombination (HR), mitigating EGFRvIII induced oncogenic stress resulting from DNA damage accumulation. Accordingly, PLK1 inhibition enhanced the cytotoxic effects of the DNA damaging agent, temozolomide (TMZ). This effect was significantly more pronounced in an Ink4a/Arf(-/-) EGFRvIII glioblastoma model relative to an Ink4a/ Arf(-/-) PDGF-β model. The tumoricidal and TMZ-sensitizing effects of BI2536 were uniformly observed across Ink4a/Arf(-/-) EGFRvIII glioblastoma clones that acquired independent resistance mechanisms to EGFR inhibitors, suggesting these resistant clones retain oncogenic stress that required PLK1 compensation. Although BI2536 significantly augmented the anti-neoplastic effect of EGFR inhibitors in the Ink4a/ Arf(-/-) EGFRvIII model, durable response was not achieved until TMZ was added. Our results suggest that optimal therapeutic effect against glioblastomas requires a {"}multi-orthogonal{"} combination tailored to the molecular physiology associated with the target cancer genome.",

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author = "Ying Shen and Jie Li and Masayuki Nitta and Diahnn Futalan and Tyler Steed and Treiber, {Jeffrey M.} and Zack Taich and Deanna Stevens and Jill Wykosky and Chen, {Hong Zhuan} and Carter, {Bob S.} and Becher, {Oren J.} and Richard Kennedy and Fumiko Esashi and Sarkaria, {Jann N.} and Furnari, {Frank B.} and Cavenee, {Webster K.} and Arshad Desai and Chen, {Clark C.}",

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T1 - Orthogonal targeting of EGFRvIII expressing glioblastomas through simultaneous EGFR and PLK1 inhibition

AU - Shen, Ying

AU - Li, Jie

AU - Nitta, Masayuki

AU - Futalan, Diahnn

AU - Steed, Tyler

AU - Treiber, Jeffrey M.

AU - Taich, Zack

AU - Stevens, Deanna

AU - Wykosky, Jill

AU - Chen, Hong Zhuan

AU - Carter, Bob S.

AU - Becher, Oren J.

AU - Kennedy, Richard

AU - Esashi, Fumiko

AU - Sarkaria, Jann N.

AU - Furnari, Frank B.

AU - Cavenee, Webster K.

AU - Desai, Arshad

AU - Chen, Clark C.

PY - 2015

Y1 - 2015

N2 - We identified a synthetic lethality between PLK1 silencing and the expression of an oncogenic Epidermal Growth Factor Receptor, EGFRvIII. PLK1 promoted homologous recombination (HR), mitigating EGFRvIII induced oncogenic stress resulting from DNA damage accumulation. Accordingly, PLK1 inhibition enhanced the cytotoxic effects of the DNA damaging agent, temozolomide (TMZ). This effect was significantly more pronounced in an Ink4a/Arf(-/-) EGFRvIII glioblastoma model relative to an Ink4a/ Arf(-/-) PDGF-β model. The tumoricidal and TMZ-sensitizing effects of BI2536 were uniformly observed across Ink4a/Arf(-/-) EGFRvIII glioblastoma clones that acquired independent resistance mechanisms to EGFR inhibitors, suggesting these resistant clones retain oncogenic stress that required PLK1 compensation. Although BI2536 significantly augmented the anti-neoplastic effect of EGFR inhibitors in the Ink4a/ Arf(-/-) EGFRvIII model, durable response was not achieved until TMZ was added. Our results suggest that optimal therapeutic effect against glioblastomas requires a "multi-orthogonal" combination tailored to the molecular physiology associated with the target cancer genome.

AB - We identified a synthetic lethality between PLK1 silencing and the expression of an oncogenic Epidermal Growth Factor Receptor, EGFRvIII. PLK1 promoted homologous recombination (HR), mitigating EGFRvIII induced oncogenic stress resulting from DNA damage accumulation. Accordingly, PLK1 inhibition enhanced the cytotoxic effects of the DNA damaging agent, temozolomide (TMZ). This effect was significantly more pronounced in an Ink4a/Arf(-/-) EGFRvIII glioblastoma model relative to an Ink4a/ Arf(-/-) PDGF-β model. The tumoricidal and TMZ-sensitizing effects of BI2536 were uniformly observed across Ink4a/Arf(-/-) EGFRvIII glioblastoma clones that acquired independent resistance mechanisms to EGFR inhibitors, suggesting these resistant clones retain oncogenic stress that required PLK1 compensation. Although BI2536 significantly augmented the anti-neoplastic effect of EGFR inhibitors in the Ink4a/ Arf(-/-) EGFRvIII model, durable response was not achieved until TMZ was added. Our results suggest that optimal therapeutic effect against glioblastomas requires a "multi-orthogonal" combination tailored to the molecular physiology associated with the target cancer genome.

KW - EGFR

KW - EGFRvIII

KW - Glioblastoma

KW - Synthetic lethality

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Orthogonal targeting of EGFRvIII expressing glioblastomas through simultaneous EGFR and PLK1 inhibition

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Keywords

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