Loss of ARID1A activates ANXA1, which serves as a predictive biomarker for trastuzumab resistance

Katrien Berns, Amir Sonnenblick, Annemiek Gennissen, Sylvain Brohée, E. Marielle Hijmans, Bastiaan Evers, Debora Fumagalli, Christine Desmedt, Sibylle Loibl, Carsten Denkert, Patrick Neven, Wei Guo, Fan Zhang, Theo A. Knijnenburg, Tjalling Bosse, Michiel S. Van Der Heijden, Sanne Hindriksen, Wouter Nijkamp, Lodewyk F.A. Wessels, Heikki Joensuu & 4 others Gordon Mills, Roderick L. Beijersbergen, Christos Sotiriou, René Bernards

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Purpose: Despite the substantial progress in the development of targeted anticancer drugs, treatment failure due to primary or acquired resistance is still a major hurdle in the effective treatment of most advanced human cancers. Understanding these resistance mechanisms will be instrumental to improve personalized cancer treatment. Experimental Design: Genome-wide loss-of-function genetic screens were performed to identify genes implicated in resistance to HER2/PI3K/mTORtargeting agents in HER2+ breast cancer cell lines. Expression and adjuvant trastuzumab response data from the HER2+ breast cancer trials FinHer and Responsify were used to validate our findings in patient series. Results: We find that reduced ARID1A expression confers resistance to several drugs that inhibit the HER2/PI3K/mTOR signaling cascade at different levels. We demonstrate that ARID1A loss activates annexin A1 (ANXA1) expression, which is required for drug resistance through its activation of AKT. We find that the AKT inhibitor MK2206 restores sensitivity of ARID1A knockdown breast cancer cells to both the mTOR kinase inhibitor AZD8055 and trastuzumab. Consistent with these in vitro data, we find in two independent HER2+ breast cancer patient series that high ANXA1 expression is associated with resistance to adjuvant trastuzumab-based therapy. Conclusions: Our findings provide a rationale for why tumors accumulate ARID1A mutations and identify high ANXA1 expression as a predictive biomarker for trastuzumab-based treatment. Our findings also suggest strategies to treat breast cancers with elevated ANXA1 expression.

Original languageEnglish (US)
Pages (from-to)5238-5248
Number of pages11
JournalClinical Cancer Research
Volume22
Issue number21
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

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Annexin A1
Biomarkers
Breast Neoplasms
Phosphatidylinositol 3-Kinases
Annexins
Neoplasms
Therapeutics
Treatment Failure
Drug Resistance
Pharmaceutical Preparations
Research Design
Phosphotransferases
Trastuzumab
Genome
Cell Line
Mutation
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Berns, K., Sonnenblick, A., Gennissen, A., Brohée, S., Hijmans, E. M., Evers, B., ... Bernards, R. (2016). Loss of ARID1A activates ANXA1, which serves as a predictive biomarker for trastuzumab resistance. Clinical Cancer Research, 22(21), 5238-5248. https://doi.org/10.1158/1078-0432.CCR-15-2996

Loss of ARID1A activates ANXA1, which serves as a predictive biomarker for trastuzumab resistance. / Berns, Katrien; Sonnenblick, Amir; Gennissen, Annemiek; Brohée, Sylvain; Hijmans, E. Marielle; Evers, Bastiaan; Fumagalli, Debora; Desmedt, Christine; Loibl, Sibylle; Denkert, Carsten; Neven, Patrick; Guo, Wei; Zhang, Fan; Knijnenburg, Theo A.; Bosse, Tjalling; Van Der Heijden, Michiel S.; Hindriksen, Sanne; Nijkamp, Wouter; Wessels, Lodewyk F.A.; Joensuu, Heikki; Mills, Gordon; Beijersbergen, Roderick L.; Sotiriou, Christos; Bernards, René.

In: Clinical Cancer Research, Vol. 22, No. 21, 01.11.2016, p. 5238-5248.

Research output: Contribution to journalArticle

Berns, K, Sonnenblick, A, Gennissen, A, Brohée, S, Hijmans, EM, Evers, B, Fumagalli, D, Desmedt, C, Loibl, S, Denkert, C, Neven, P, Guo, W, Zhang, F, Knijnenburg, TA, Bosse, T, Van Der Heijden, MS, Hindriksen, S, Nijkamp, W, Wessels, LFA, Joensuu, H, Mills, G, Beijersbergen, RL, Sotiriou, C & Bernards, R 2016, 'Loss of ARID1A activates ANXA1, which serves as a predictive biomarker for trastuzumab resistance', Clinical Cancer Research, vol. 22, no. 21, pp. 5238-5248. https://doi.org/10.1158/1078-0432.CCR-15-2996
Berns, Katrien ; Sonnenblick, Amir ; Gennissen, Annemiek ; Brohée, Sylvain ; Hijmans, E. Marielle ; Evers, Bastiaan ; Fumagalli, Debora ; Desmedt, Christine ; Loibl, Sibylle ; Denkert, Carsten ; Neven, Patrick ; Guo, Wei ; Zhang, Fan ; Knijnenburg, Theo A. ; Bosse, Tjalling ; Van Der Heijden, Michiel S. ; Hindriksen, Sanne ; Nijkamp, Wouter ; Wessels, Lodewyk F.A. ; Joensuu, Heikki ; Mills, Gordon ; Beijersbergen, Roderick L. ; Sotiriou, Christos ; Bernards, René. / Loss of ARID1A activates ANXA1, which serves as a predictive biomarker for trastuzumab resistance. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 21. pp. 5238-5248.
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abstract = "Purpose: Despite the substantial progress in the development of targeted anticancer drugs, treatment failure due to primary or acquired resistance is still a major hurdle in the effective treatment of most advanced human cancers. Understanding these resistance mechanisms will be instrumental to improve personalized cancer treatment. Experimental Design: Genome-wide loss-of-function genetic screens were performed to identify genes implicated in resistance to HER2/PI3K/mTORtargeting agents in HER2+ breast cancer cell lines. Expression and adjuvant trastuzumab response data from the HER2+ breast cancer trials FinHer and Responsify were used to validate our findings in patient series. Results: We find that reduced ARID1A expression confers resistance to several drugs that inhibit the HER2/PI3K/mTOR signaling cascade at different levels. We demonstrate that ARID1A loss activates annexin A1 (ANXA1) expression, which is required for drug resistance through its activation of AKT. We find that the AKT inhibitor MK2206 restores sensitivity of ARID1A knockdown breast cancer cells to both the mTOR kinase inhibitor AZD8055 and trastuzumab. Consistent with these in vitro data, we find in two independent HER2+ breast cancer patient series that high ANXA1 expression is associated with resistance to adjuvant trastuzumab-based therapy. Conclusions: Our findings provide a rationale for why tumors accumulate ARID1A mutations and identify high ANXA1 expression as a predictive biomarker for trastuzumab-based treatment. Our findings also suggest strategies to treat breast cancers with elevated ANXA1 expression.",
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AU - Berns, Katrien

AU - Sonnenblick, Amir

AU - Gennissen, Annemiek

AU - Brohée, Sylvain

AU - Hijmans, E. Marielle

AU - Evers, Bastiaan

AU - Fumagalli, Debora

AU - Desmedt, Christine

AU - Loibl, Sibylle

AU - Denkert, Carsten

AU - Neven, Patrick

AU - Guo, Wei

AU - Zhang, Fan

AU - Knijnenburg, Theo A.

AU - Bosse, Tjalling

AU - Van Der Heijden, Michiel S.

AU - Hindriksen, Sanne

AU - Nijkamp, Wouter

AU - Wessels, Lodewyk F.A.

AU - Joensuu, Heikki

AU - Mills, Gordon

AU - Beijersbergen, Roderick L.

AU - Sotiriou, Christos

AU - Bernards, René

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N2 - Purpose: Despite the substantial progress in the development of targeted anticancer drugs, treatment failure due to primary or acquired resistance is still a major hurdle in the effective treatment of most advanced human cancers. Understanding these resistance mechanisms will be instrumental to improve personalized cancer treatment. Experimental Design: Genome-wide loss-of-function genetic screens were performed to identify genes implicated in resistance to HER2/PI3K/mTORtargeting agents in HER2+ breast cancer cell lines. Expression and adjuvant trastuzumab response data from the HER2+ breast cancer trials FinHer and Responsify were used to validate our findings in patient series. Results: We find that reduced ARID1A expression confers resistance to several drugs that inhibit the HER2/PI3K/mTOR signaling cascade at different levels. We demonstrate that ARID1A loss activates annexin A1 (ANXA1) expression, which is required for drug resistance through its activation of AKT. We find that the AKT inhibitor MK2206 restores sensitivity of ARID1A knockdown breast cancer cells to both the mTOR kinase inhibitor AZD8055 and trastuzumab. Consistent with these in vitro data, we find in two independent HER2+ breast cancer patient series that high ANXA1 expression is associated with resistance to adjuvant trastuzumab-based therapy. Conclusions: Our findings provide a rationale for why tumors accumulate ARID1A mutations and identify high ANXA1 expression as a predictive biomarker for trastuzumab-based treatment. Our findings also suggest strategies to treat breast cancers with elevated ANXA1 expression.

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