PO-201 Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase

Abstract

IntroductionThe ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors. Its requirement for complete RAS-MAPK activation and its role as a negative regulator of JAK-STAT signalling have established SHP2 as an essential player in oncogenic signalling pathways. Recently, novel potent allosteric SHP2-inhibitors have been presented as a viable therapeutic option for RTK-driven cancers, but were shown to be ineffective in KRAS mutant tumour cell lines in vitro.Material and methodsVarious mutant KRAS-driven murine models of pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) were employed to investigate the contribution of Ptpn11/SHP2 to carcinogenesis and tumour maintenance, and to determine its utility as a therapeutic target for treatment of established tumours in vivo. CRISPR/Cas9 mediated knockout of PTPN11 in human PDAC cell lines, drug-synergy screening and human PDAC organoid and tissue xenograft model therapeutic trials substantiated the rationale of dual SHP2/MEK inhibition in a human context.Results and discussionsWe report a central and indispensable role for SHP2 in oncogenic KRAS-driven tumours. Genetic deletion of Ptpn11 profoundly inhibited tumour development in mutant KRAS-driven murine models PDAC and NSCLC. We provide evidence for a critical dependence of mutant KRAS on SHP2 during carcinogenesis. Deletion or inhibition of SHP2 in established tumours delayed tumour progression but was not sufficient to achieve tumour regression. However, SHP2 was necessary for resistance mechanisms upon blockade of MEK. Synergy was observed when both SHP2 and MEK were targeted, resulting in sustained tumour growth control in murine and human patient-derived organoids and xenograft models of PDAC and NSCLC.ConclusionOur data suggest clinical utility of dual SHP2/MEK inhibition as a targeted therapy approach for KRAS mutant cancers.