{'fraction_non_alphanumeric': 0.031914893617021274, 'fraction_numerical': 0.03292806484295846, 'mean_word_length': 5.454248366013072, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Abstract 4346: PI3K pathway mediated splicing defects in ER+ breast cancers

Activating mutations in PIK3CA, the gene encoding for the catalytic subunit (p100a), are the most common oncogenic alterations in estrogen receptor-positive (ER+). The majority of PIK3CA mutations occur within two hot spots; exons 9 and exon 20 which encode the helical (E545K) and kinase domains (H1047R), respectively. These mutations result in hyperactivation of the PI3K/AKT/mTOR pathway and provide the rationale for the development of inhibitors targeting the PI3K pathway. To this end, PI3K α-specific inhibitors are showing antitumor activity in patients with PIK3CA-mutant, ER-positive breast cancer. Evidence of alternative mRNA regulation and splicing in various cancers has been described in the literature. Although, the majority of events appear to have unknown clinical significance, there is evidence alternative splicing can lead to drug resistance. The role of the PI3K pathway on transcriptional regulation and mRNA processing is not well studied. Through transcriptome analysis and cell assays in mouse MEF and human MCF10A cells we demonstrate splicing defects accrue as a result of the PI3K pathway activation by the PIK3CA H1047R mutation. PI3Ka pathway inhibitors were able to restore wildtype exon inclusion levels in these mutants, suggesting a potential clinical benefit. We propose that PIK3CA H1047R imposes mRNA differential isoform regulation by acting through the most commonly mutated PI3K pathway in ER+ breast cancers and that such mutations are targetable with PI3K pathway inhibitors. Citation Format: Erik Ladewig, Lauren Fairchild, Maurizio Scaltriti, Christina Leslie, Eneda Toska, Jose Baselga. PI3K pathway mediated splicing defects in ER+ breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4346.