Credit: Neil Smith

The behaviour and clinical response of tumours is largely determined by the combinations of mutations that drive their progression. The PI3K–AKT kinase pathway is a downstream effector of RAS family member signalling, suggesting that tumours should gain no selective advantage from mutations in both the RAS and the PI3K–AKT signalling axes. However, mutations in both are found in the same human tumours, and a new study might explain why: PI3K–AKT activation can bypass the senescence response to deregulated RAS signalling.

Biallelic loss of Pten (a negative PI3K regulator) concurrent with KRAS activation ... dramatically accelerated tumour progression.

To characterize the different consequences of activation of RAS compared with AKT, Peter Adams, Owen Sansom and colleagues ectopically expressed constitutively active HRAS-G12V or myristoylated AKT1 (myr-AKT1) in primary human fibroblasts. As expected, HRAS-G12V induced a potent senescence response, as determined by several different markers of senescence, and resulted in irreversible cell cycle arrest. By contrast, myr-AKT1 caused a weak, impaired senescence response.

Examining their combined effects, co-expression of HRAS-G12V and myr-AKT1 revealed that activated AKT1 antagonized, rather than enhanced, the potent HRAS-mediated senescence programme. As possible mechanisms for this senescence bypass, the authors noticed that myr-AKT1 led to an activating phosphorylation of mTOR (a potent repressor of autophagy, which is a senescence effector process) and an inactivating phosphorylation of glycogen synthase kinase 3β (GSK3B), the activity of which is required for the characteristic chromatin alterations that are evident during senescence.

To study senescence bypass in vivo, the authors used a mouse model of senescent pancreatic intraepithelial neoplasia (PanIN) that was driven by KRAS-G12D. Biallelic loss of Pten (a negative PI3K regulator) concurrent with KRAS activation led to activated AKT signalling, abolishment of KRAS-induced senescence markers, increased cell proliferation and dramatically accelerated tumour progression. This emphasizes the importance of PI3K–AKT signalling for overcoming senescence in vivo. Alluding to a potential therapeutic intervention, treatment with rapamycin (an mTOR inhibitor) restored several senescence markers in these tumours, although it is unclear whether rapamycin treatment could improve the survival of mice or humans with RAS-driven cancers. However, immunohistochemical staining of human pancreatic cancer tissue microarrays revealed that increased staining for phosphorylated forms of AKT1 and GSK3B correlated with decreased patient survival.

It will be interesting to determine whether subsequent AKT activation can reverse established RAS-induced senescence and whether mutations in the PI3K–AKT pathway in human RAS-driven tumours diminish the requirement for other senescence-bypassing lesions such as mutations in TP53 or RB1.