Persistent activation of the mammalian target of rapamycin signalling pathway in cutaneous squamous cell carcinomas in cats

. SANZ RESSEL BL, MASSONE AR, BARBEITO CG

Sidney

Congreso; 9th World Congress of Veterinary Dermatology; 2020

ESVD and ACVD

Cutaneous squamous cell carcinoma (CSCC) representsthe most common malignant tumour of the feline skin.Research aimed at clarifying how the deregulated activityof signalling pathways contributes to CSCC progressioncan help to identify suitable molecular targets forthe development of novel therapeutic approaches. Inthis regard, recent evidence indicates that the developmentand progression of human CSCC involve the dysregulatedactivation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling pathway, which is a key regulator ofcell growth and cell fate. Thus, the present study investigatedthe immunohistochemical expression pattern ofrelevant signalling proteins involved in the PI3K/Akt/mTOR signalling pathway including, pEGFRTyr1068,pAktSer473, pS6Ser235/236 combined with Ki-67, and thetumour suppressor protein PTEN. These signalling proteinswere investigated in 45 feline CSCC samples usinga tissue microarray. In normal feline skin controls, allproteins showed a low expression in the epidermis,except pEGFRTyr1068. In CSCC, pEGFRTyr1068 immunodetectionshowed that the persistent activation of thisreceptor was a frequent event in 31 of 45 samples,showing membrane and cytoplasmic immunoreactivityin the epidermal cells of the basal and spinous strata.Likewise, pAktSer473 was overexpressed in 30 of 45CSCC samples, showing cytoplasmic and nuclearimmunoreactivity in the basal and suprabasal cellstrata. Forty-one of 45 CSCC samples also showed ahigh epidermal expression for pS6Ser235/236, with manyof the cells having cytoplasmic staining located in thebasal and parabasal cells strata. Indeed, the doubleimmunostaining of pS6Ser235/236 combined with the proliferationmarker Ki-67 showed the co-expression ofthese molecules in some basal and parabasal neoplasticcells of most CSCC samples, a finding that was notobserved in normal feline skin. We also have identifieda group of CSCC feline patients displaying active Aktand S6 in the absence of EGFR activation. Expressionof PTEN characterized by a cytoplasmic immunoreactivityin the basal and spinous cell strata was reducedor absent in 15 of 45 CSCC samples. These findingsshow that the persistent activation of the PI3K/Akt/mTOR signalling pathway represents one of the keyevents during CSCC progression in cats, pointing tothis signalling pathway as a potential therapeutic targetin CSCC feline patients. These results also demonstratethat the activation of the PI3K/Akt/mTOR signallingpathway is independent from EGFR activation in somefeline CSCC, suggesting that therapeutic approachesaimed at modulating the growth and survival oftumour cells by the use of EGFR inhibitors would beineffective as sole therapeutic agents in some CSCCfeline patients.