Reference Detail

Ref Type

Journal Article

PMID

(27172896)

Authors

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 LF, Joensuu H, Mills GB, Beijersbergen RL, Sotiriou C, Bernards R

Title

Loss of ARID1A Activates ANXA1, which Serves as a Predictive Biomarker for Trastuzumab Resistance.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	22	21	2016 Nov 01	5238-5248	Clin Cancer Res

URL

Abstract Text

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.Genome-wide loss-of-function genetic screens were performed to identify genes implicated in resistance to HER2/PI3K/mTOR targeting 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.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.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. Clin Cancer Res; 22(21); 5238-48. ©2016 AACR.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ARID1A loss	breast cancer	sensitive	AZD8055 + MK2206	Preclinical - Cell culture	Actionable	In a preclinical study, breast cancer cells with loss of ARID1A demonstrated restored sensitivity to AZD8055 when additionally treated with MK2206 in culture (PMID: 27172896).	27172896
ARID1A loss	Her2-receptor positive breast cancer	resistant	AZD8055	Preclinical - Cell culture	Actionable	In a preclinical study, ERBB2 (HER2) positive breast cancer cells with ARID1A loss demonstrated resistance to AZD8055 in culture (PMID: 27172896).	27172896
ARID1A loss	Her2-receptor positive breast cancer	resistant	Trastuzumab	Preclinical - Cell culture	Actionable	In a preclinical study, ERBB2 (HER2) positive breast cancer cells with ARID1A loss demonstrated resistance to Herceptin (trastuzumab) in culture (PMID: 27172896).	27172896