PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer

Abbie E Fearon; Edward P Carter; Natasha S Clayton; Edmund H Wilkes; Ann-Marie Baker; Ekaterina Kapitonova; Bakhouche A Bakhouche; Yasmine Tanner; Jun Wang; Emanuela Gadaleta; Claude Chelala; Kate M Moore; John F Marshall; Juliette Chupin; Peter Schmid; J Louise Jones; Michelle Lockley; Pedro R Cutillas; Richard P Grose

doi:10.1016/j.celrep.2018.02.028

PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer

Abbie E Fearon, Edward P Carter, Natasha S Clayton, Edmund H Wilkes, Ann-Marie Baker, Ekaterina Kapitonova, Bakhouche A Bakhouche, Yasmine Tanner, Jun Wang, Emanuela Gadaleta, Claude Chelala, Kate M Moore, John F Marshall, Juliette Chupin, Peter Schmid, J Louise Jones, Michelle Lockley, Pedro R Cutillas, Richard P Grose

Department of Life Sciences

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

36 Citations (SciVal)

Abstract

Development of resistance causes failure of drugs targeting receptor tyrosine kinase (RTK) networks and represents a critical challenge for precision medicine. Here, we show that PHLDA1 downregulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using fibroblast growth factor receptor (FGFR) inhibition in endometrial cancer cells, we identify an Akt-driven compensatory mechanism underpinned by downregulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 downregulation also occurs in response to RTK-targeted therapy in breast and renal cancer patients, as well as following trastuzumab treatment in HER2+ breast cancer cells. Crucially, knockdown of PHLDA1 alone was sufficient to confer de novo resistance to RTK inhibitors and induction of PHLDA1 expression re-sensitized drug-resistant cancer cells to targeted therapies, identifying PHLDA1 as a biomarker for drug response and highlighting the potential of PHLDA1 reactivation as a means of circumventing drug resistance.

Original language	English
Pages (from-to)	2469-2481
Number of pages	13
Journal	Cell Reports
Volume	22
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2018.02.028
Publication status	Published - 27 Feb 2018

Bibliographical note

Keywords

Cell Line, Tumor
Down-Regulation/drug effects
Drug Resistance, Neoplasm/drug effects
Endometrial Neoplasms/metabolism
Female
Gene Expression Regulation, Neoplastic/drug effects
Gene Knockdown Techniques
Humans
Lapatinib/pharmacology
Models, Biological
Phosphoproteins/metabolism
Protein Kinase Inhibitors/pharmacology
Proteomics
Receptors, Fibroblast Growth Factor/metabolism
Transcription Factors/genetics
Trastuzumab/pharmacology

UN SDGs

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

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10.1016/j.celrep.2018.02.028Licence: CC BY

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Fearon, A. E., Carter, E. P., Clayton, N. S., Wilkes, E. H., Baker, A.-M., Kapitonova, E., Bakhouche, B. A., Tanner, Y., Wang, J., Gadaleta, E., Chelala, C., Moore, K. M., Marshall, J. F., Chupin, J., Schmid, P., Jones, J. L., Lockley, M., Cutillas, P. R., & Grose, R. P. (2018). PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer. Cell Reports, 22(9), 2469-2481. https://doi.org/10.1016/j.celrep.2018.02.028

Fearon, AE, Carter, EP, Clayton, NS, Wilkes, EH, Baker, A-M, Kapitonova, E, Bakhouche, BA, Tanner, Y, Wang, J, Gadaleta, E, Chelala, C, Moore, KM, Marshall, JF, Chupin, J, Schmid, P, Jones, JL, Lockley, M, Cutillas, PR & Grose, RP 2018, 'PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer', Cell Reports, vol. 22, no. 9, pp. 2469-2481. https://doi.org/10.1016/j.celrep.2018.02.028

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abstract = "Development of resistance causes failure of drugs targeting receptor tyrosine kinase (RTK) networks and represents a critical challenge for precision medicine. Here, we show that PHLDA1 downregulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using fibroblast growth factor receptor (FGFR) inhibition in endometrial cancer cells, we identify an Akt-driven compensatory mechanism underpinned by downregulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 downregulation also occurs in response to RTK-targeted therapy in breast and renal cancer patients, as well as following trastuzumab treatment in HER2+ breast cancer cells. Crucially, knockdown of PHLDA1 alone was sufficient to confer de novo resistance to RTK inhibitors and induction of PHLDA1 expression re-sensitized drug-resistant cancer cells to targeted therapies, identifying PHLDA1 as a biomarker for drug response and highlighting the potential of PHLDA1 reactivation as a means of circumventing drug resistance.",

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AU - Fearon, Abbie E

AU - Carter, Edward P

AU - Clayton, Natasha S

AU - Wilkes, Edmund H

AU - Baker, Ann-Marie

AU - Kapitonova, Ekaterina

AU - Bakhouche, Bakhouche A

AU - Tanner, Yasmine

AU - Wang, Jun

AU - Gadaleta, Emanuela

AU - Chelala, Claude

AU - Moore, Kate M

AU - Marshall, John F

AU - Chupin, Juliette

AU - Schmid, Peter

AU - Jones, J Louise

AU - Lockley, Michelle

AU - Cutillas, Pedro R

AU - Grose, Richard P

PY - 2018/2/27

Y1 - 2018/2/27

N2 - Development of resistance causes failure of drugs targeting receptor tyrosine kinase (RTK) networks and represents a critical challenge for precision medicine. Here, we show that PHLDA1 downregulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using fibroblast growth factor receptor (FGFR) inhibition in endometrial cancer cells, we identify an Akt-driven compensatory mechanism underpinned by downregulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 downregulation also occurs in response to RTK-targeted therapy in breast and renal cancer patients, as well as following trastuzumab treatment in HER2+ breast cancer cells. Crucially, knockdown of PHLDA1 alone was sufficient to confer de novo resistance to RTK inhibitors and induction of PHLDA1 expression re-sensitized drug-resistant cancer cells to targeted therapies, identifying PHLDA1 as a biomarker for drug response and highlighting the potential of PHLDA1 reactivation as a means of circumventing drug resistance.

AB - Development of resistance causes failure of drugs targeting receptor tyrosine kinase (RTK) networks and represents a critical challenge for precision medicine. Here, we show that PHLDA1 downregulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using fibroblast growth factor receptor (FGFR) inhibition in endometrial cancer cells, we identify an Akt-driven compensatory mechanism underpinned by downregulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 downregulation also occurs in response to RTK-targeted therapy in breast and renal cancer patients, as well as following trastuzumab treatment in HER2+ breast cancer cells. Crucially, knockdown of PHLDA1 alone was sufficient to confer de novo resistance to RTK inhibitors and induction of PHLDA1 expression re-sensitized drug-resistant cancer cells to targeted therapies, identifying PHLDA1 as a biomarker for drug response and highlighting the potential of PHLDA1 reactivation as a means of circumventing drug resistance.

KW - Cell Line, Tumor

KW - Down-Regulation/drug effects

KW - Drug Resistance, Neoplasm/drug effects

KW - Endometrial Neoplasms/metabolism

KW - Female

KW - Gene Expression Regulation, Neoplastic/drug effects

KW - Gene Knockdown Techniques

KW - Humans

KW - Lapatinib/pharmacology

KW - Models, Biological

KW - Phosphoproteins/metabolism

KW - Protein Kinase Inhibitors/pharmacology

KW - Proteomics

KW - Receptors, Fibroblast Growth Factor/metabolism

KW - Transcription Factors/genetics

KW - Trastuzumab/pharmacology

U2 - 10.1016/j.celrep.2018.02.028

DO - 10.1016/j.celrep.2018.02.028

M3 - Article

C2 - 29490281

SN - 2211-1247

VL - 22

SP - 2469

EP - 2481

JO - Cell Reports

JF - Cell Reports

IS - 9

ER -

PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer

Abstract

Bibliographical note

Keywords

UN SDGs

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