Combination of PI3K and MEK inhibitors yields durable remission in PDX models of PIK3CA-mutated metaplastic breast cancers

Abstract

Background: Metaplastic breast cancer (MBC) is a rare form of breast cancer characterized by an aggressive clinical presentation, with a poor response to standard chemotherapy. MBCs are typically triple-negative breast cancers (TNBCs), frequently with alterations to genes of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways. The objective of this study was to determine the response to PI3K and MAPK pathway inhibitors in patient-derived xenografts (PDXs) of MBCs with targetable alterations. Methods: We compared survival between triple-negative MBCs and other histological subtypes, in a clinical cohort of 323 TNBC patients. PDX models were established from primary breast tumors classified as MBC. PI3K-AKT-mTOR and RTK-MAPK pathway alterations were detected by targeted next-generation sequencing (NGS) and analyses of copy number alterations. Activation of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways was analyzed with reverse-phase protein arrays (RPPA). PDXs carrying an activating mutation of PIK3CA and genomic changes to the RTK-MAPK signaling pathways were treated with a combination consisting of a PI3K inhibitor and a MEK inhibitor. Results: In our clinical cohort, the patients with MBC had a worse prognosis than those with other histological subtypes. We established nine metaplastic TNBC PDXs. Three had a pathogenic mutation of PIK3CA and additional alterations to genes associated with RTK-MAPK signaling. The MBC PDXs expressed typical EMT and stem cell genes and were of the mesenchymal or mesenchymal stem-like TNBC subtypes. On histological analysis, MBC PDXs presented squamous or chondroid differentiation. RPPA analysis showed activation of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways. In vivo, the combination of PI3K and MAPK inhibitors displayed marked antitumor activity in PDXs carrying genomic alterations of PIK3CA, AKT1, BRAF, and FGFR4. Conclusion: The treatment of metaplastic breast cancer PDXs by activation of the PI3K-AKT-mTOR and RTK-MAPK pathways at the genomic and protein levels with a combination of PI3K and MEK inhibitors resulted in tumor regression in mutated models and may therefore be of interest for therapeutic purposes.

The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy

“…Although hyperactive MAPK signaling has a dominant role in cancer biology, it is fine-tuned by other signalings such as PI3K/AKT/mTORC and AMPK during disease progression [ 133 ]. These signaling interplays have important impacts on both cancer progression and clinical treatment based on MAPK inhibition.…”

Nanoparticle-Encapsulated Camptothecin: Epigenetic Modulation in DNA Repair Mechanisms in Colon Cancer Cells

“…Reduced activity of HMGB1 leads to higher frequency of DNA damage when exposed to radiation, carcinogens, or chemotherapeutic or oxidative stress-inducing agents [ 32 ]. It can translocate from the nucleus to the cytoplasm following post-translational modifications, including acetylation, phosphorylation, and methylation [ 33 ]. The secretion of HMGB1 from cells can trigger a cascade of inflammatory reactions.…”

RASAL2 Confers Collateral MEK/EGFR Dependency in Chemoresistant Triple-Negative Breast Cancer

“…For instance, a recent Phase 2 trial evaluating MEKi and AKTi showed limited efficacy of this combination in unselected advanced TNBC patients, although a small number of clinical responses were observed (9). In contrast, in patient-derived xenograft models of (rare) metaplastic TNBC harboring both PI3K/AKT/mTOR and RTK/MAPK alterations, MEKi and PI3Ki induced tumor regression, suggesting that targeting MEK and PI3K/AKT is a potentially viable strategy under specific contexts (55). In TNBC cell lines, co-targeting MEK1/2 and EGFR has been shown to induce synergistic growth inhibition and apoptosis, albeit to varying degrees (56).…”