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Theranostics 2020; 10(4):1531-1543. doi:10.7150/thno.36182 This issue Cite

Research Paper

Response to mTOR and PI3K inhibitors in enzalutamide-resistant luminal androgen receptor triple-negative breast cancer patient-derived xenografts

Florence Coussy^1,2,3✉, Marion Lavigne⁴, Leanne de Koning⁵, Rania El Botty², Fariba Nemati², Adnan Naguez², Guillaume Bataillon⁴, Berengère Ouine⁵, Ahmed Dahmani², Elodie Montaudon², Pierre Painsec², Sophie Chateau-Joubert⁶, Fuhrmann Laetitia⁴, Thibaut Larcher⁷, Sophie Vacher¹, Walid Chemlali¹, Adrien Briaux¹, Samia Melaabi¹, Anne Vincent Salomon⁴, Jean Marc Guinebretiere⁸, Ivan Bieche^1,9*, Elisabetta Marangoni^2*

1. Unit of Pharmacogenomics, Department of Genetics, Institut Curie, 26 rue d'Ulm, Paris, France
2. Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie Research Center, 26 rue d' Ulm, Paris, France
3. Department of Medical Oncology, Institut Curie, 26 rue d' Ulm, Paris, France
4. Department of Biopathology, Institut Curie, 26 rue d' Ulm, Paris, France
5. Translational Research Department, RPPA Platform, Institut Curie Research Center, 26 rue d'Ulm, Paris, France
6. BioPôle Alfort, National Veterinary School of Alfort, Maison Alfort, France
7. INRA, APEX-PAnTher, Oniris, Nantes, France
8. Department of Biopathology, Institut Curie, Hopital René Huguenin, Saint Cloud, France
9. U1016, Paris Descartes University, 4 avenue de l'observatoire, Paris, France.
*Contributed equally

✉ Corresponding author: Florence Coussy. E-mail: florence.coussyfr; Phone: + 33 1 56245841; Fax: + 33 1 53 10 26 65.

Abstract

Luminal androgen receptor (LAR) breast cancer accounts for 10% of all triple-negative breast cancers (TNBC). Anti-androgen therapy for this subtype is in development, but yields only partial clinical benefits. In this study, we aimed to characterize the genomic alterations of LAR TNBC, to analyze activation of the PI3K signaling pathway and to compare the response to PI3K pathway inhibitors with that to anti-androgen therapy in patient-derived xenografts (PDX) of LAR TNBC.

Methods: Four LAR PDX models were identified, on the basis of their transcriptomic profiles, in a cohort of 57 PDX models of TNBC. The expression of AR-related genes, basal and luminal cytokeratins and EMT genes was analyzed by RT-PCR and IHC. AKT1 and PIK3CA mutations were identified by targeted NGS, and activation of the PI3K pathway was analyzed with a reverse-phase protein array. Three LAR PDXs with a PIK3CA or AKT1 mutation were treated with the AR inhibitor enzalutamide, a PI3K inhibitor, a dual PI3K-mTOR inhibitor and a mTORC1-mTORC2 inhibitor. Finally, we screened a clinical cohort of 329 TNBC for PIK3CA and AKT1 hotspot mutations.

Results: LAR TNBC PDXs were significantly enriched in PIK3CA and AKT1 mutations, and had higher levels of luminal-androgen-like gene expression and a higher PI3K pathway protein activation score than other TNBC subtypes. Immunohistochemistry analysis revealed strong expression of the luminal cytokeratin CK18 and AR in three LAR PDX models. We found that mTOR and PI3K inhibitors had marked antitumor activity in vivo in PDX harboring genomic alterations of PIK3CA and AKT1 genes that did not respond to the AR antagonist enzalutamide. PIK3CA mutations were detected in more than one third of AR+ TNBC from patients (38%), and only 10% of AR-negative TNBC.

Conclusion: Our results for PDX models of LAR TNBC resistant to enzalutamide indicate that PIK3CA and AKT1 are potential therapeutic targets.

Keywords: Triple-negative breast cancer, androgen receptor, luminal androgen receptor (LAR), genomic alteration, targeted therapy, PI3K pathway inhibitor.

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