PIK3CA and KRAS co-activation synergise to promote prostate cancer progression
Session type: Poster / e-Poster / Silent Theatre session
Prostate cancer is the fifth cause of cancer-related deaths in men globally, reflecting resistance to standard clinical regimens(1). Thus, there is an urgent need to improve our understanding of the molecular mechanisms underpinning prostate cancer, and to identify new therapeutic approaches to improve our management of this disease. The PI3K and RAS pathways regulate AKT/mTOR and MAPK signalling to mediate cell growth/survival/migration and are invariably activated in advanced prostate cancer, thus presenting attractive therapeutic targets(2,3). Although oncogenic PI3K/RAS signalling are common in prostate cancer, how these cascades synergise to promote prostate cancer growth remains unclear.
To determine how PI3K/RAS signalling cooperate to accelerate prostate cancer growth in vivo, we employed a conditional transgenic approach to co-activate Pik3ca and KRas in murine prostate epithelium. We compared prostate histopathology/survival relative to single mutants and prostate tumours were comprehensively characterised using molecular assays and chemical inhibition studies performed to delineate the synergistic relationship between PI3K/RAS signalling.
We show that simultaneous expression of oncogenic Pik3ca and KRas mutations in the murine prostate causes rapid formation of locally invasive prostate carcinoma compared to single mutants. We report that the observed synergy is associated with elevated proliferation and apoptosis evasion, which is not simply a consequence of augmented PI3K or MAPK signalling. Importantly, chemical inhibition of the PI3K and MAPK pathways indicates that targeting these cascades using pan-PI3K/mTORC1 and/or MEK inhibitors respectively only marginally reduces tumor burden in this setting.
Our findings indicate that Pik3ca activation and oncogenic KRas synergise in vivo to accelerate prostate cancer progression, and that pan-PI3K/mTORC1 and/or MEK inhibition shows limited therapeutic efficacy in this model. Establishing the molecular events that underpin the observed synergy and therapeutic resistance may present new therapeutic approaches to combat prostate cancer.
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