Abstract 4290
Background
The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer. Mutations in PIK3CA, the gene coding the p110α catalytic subunit of PI3K, are frequent in cancer and result in PI3K pathway activation. About 25% of HER2-positive breast cancers also carry PIK3CA mutations, known to confer resistance to anti-HER2 therapy. Here we report the preclinical characterization of MEN1611, a potent and selective orally available PI3K inhibitor, showing high activity against p110α mutant isoforms and sparing the δ isoform.
Methods
In vivo efficacy studies were evaluated through Tumour Volume Inhibition % (TVI%) and mRECIST criteria using cancer cell lines and patient-derived xenograft (PDX) models. Pathway activation and protein degradation analyses were performed by western blot and capillary electrophoresis immunoassay. Immune modulation was evaluated using murine macrophages differentiated in vitro.
Results
Consistent with its mechanism of action, MEN1611 down-modulates the PI3K/AKT signaling as well as selected downstream targets, both in vitro and in vivo. MEN1611 acts synergistically when combined with trastuzumab in several HER2-positive PIK3CA-mutated breast cancer cell lines and patient-derived xenograft models. The in vivo efficacy in trastuzumab-resistant models is supported by a long-lasting antitumor activity, paralleled by mechanistic down-regulation of pharmacodynamic biomarkers. Moreover, MEN1611 showed the ability to induce a dose-dependent alpha-isoform depletion, and to modulate the macrophage polarization towards a pro-inflammatory phenotype, consistent with its capability to co-inhibit P110γ.
Conclusions
Overall, these preclinical data support the progression in the development of MEN1611 in breast cancer and pave the way to the B-Precise-01 clinical study, a multicentre phase Ib study.
Clinical trial identification
NCT03767335.
Editorial acknowledgement
Legal entity responsible for the study
Menarini Ricerche S.p.A.
Funding
Menarini Ricerche S.p.A.
Disclosure
A. Fiascarelli: Full / Part-time employment: Menarini RIcerche S.p.A. G. Merlino: Full / Part-time employment: Menarini Ricerche S.p.A. S. Capano: Full / Part-time employment: Menarini Ricerche S.p.A. A. Paoli: Full / Part-time employment: Menarini Ricerche S.p.A.. A. Bressan: Full / Part-time employment: Menarini Ricerche. M. Bigioni: Full / Part-time employment: Menarini Ricerche S.p.A.. M. Scaltriti: Advisory / Consultancy: Memorial Sloan-Kettering Cancer Center. J. Arribas: Advisory / Consultancy: Vall d’Hebron Institute of Oncology. C. Bernadó Morales: Advisory / Consultancy: Vall d’Hebron Institute of Oncology. A. Pellacani: Leadership role, Full / Part-time employment: Menarini Ricerche S.p.A.. M. Salerno: Leadership role, Full / Part-time employment: Menarini Ricerche. M. Binaschi: Leadership role, Full / Part-time employment: Menarini Ricerche S.p.A.
Resources from the same session
3264 - A novel preclinical model of RAF-independent MEK1 mutant tumors and its treatment with novel ATP competitive MEK inhibitor
Presenter: Luca Hegedus
Session: Poster Display session 3
Resources:
Abstract
4918 - HER2 inhibition in Aggressive Squamous Cell Carcinomas driven by a common MET Sema Domain Polymorphism
Presenter: Nur Afiqah Mohamed Salleh
Session: Poster Display session 3
Resources:
Abstract
2426 - ADAM9 as a target for lung cancer treatment
Presenter: Yuh-pyng Sher
Session: Poster Display session 3
Resources:
Abstract
5537 - Novel polyurea/polyurethane nanocapsules loaded with a tambjamine analog to improve cancer chemotherapy delivery and safety in lung cancer
Presenter: Marta Perez Hernandez
Session: Poster Display session 3
Resources:
Abstract
1597 - Discovery of Clinical Candidate DBPR112, a Furanopyrimidine-based Epidermal Growth Factor Receptor Inhibitor for the Treatment of Non-Small Cell Lung Cancer
Presenter: Hsing-pang Hsieh
Session: Poster Display session 3
Resources:
Abstract
3543 - Molecular characteristics in lung squamous cell carcinomas dependent on TP53 status – putative targets
Presenter: Vilde Haakensen
Session: Poster Display session 3
Resources:
Abstract
4111 - Comparison of molecular profiles between primary tumour and matched metastasis in non-small cell lung cancer
Presenter: Asuka Kawachi
Session: Poster Display session 3
Resources:
Abstract
4559 - Treatment with BLU-667, a potent and selective RET inhibitor, provides rapid clearance of ctDNA in Patients with RET-altered Non-Small Cell Lung Cancer (NSCLC) and Thyroid Cancer
Presenter: Giuseppe Curigliano
Session: Poster Display session 3
Resources:
Abstract
2501 - Triple MET/SRC/PIM inhibition in MET addicted tumors
Presenter: Ilaria Attili
Session: Poster Display session 3
Resources:
Abstract
5655 - Bioactivation of napabucasin triggers reactive oxygen species–mediated cancer cell death
Presenter: Fieke Froeling
Session: Poster Display session 3
Resources:
Abstract