Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase

Abstract

The 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 signaling have established SHP2 as an essential player in oncogenic signaling pathways. Recently, a novel potent allosteric SHP2 inhibitor was presented as a viable therapeutic option for receptor tyrosine kinase-driven cancers, but was shown to be ineffective in KRAS-mutant tumor cell lines in vitro. Here, we report a central and indispensable role for SHP2 in oncogenic KRAS-driven tumors. Genetic deletion of Ptpn11 profoundly inhibited tumor development in mutant KRAS-driven murine models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. We provide evidence for a critical dependence of mutant KRAS on SHP2 during carcinogenesis. Deletion or inhibition of SHP2 in established tumors delayed tumor progression but was not sufficient to achieve tumor 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 tumor growth control in murine and human patient-derived organoids and xenograft models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. Our data indicate the clinical utility of dual SHP2/MEK inhibition as a targeted therapy approach for KRAS-mutant cancers.

A network analysis revealed the essential and common downstream proteins related to inguinal hernia

“…The GO term analysis also indicated that protein tyrosine kinase activity, transmembrane RTK activity, phosphatidylinositol-4,5-bisphosphate 3-kinase activity, as well as binding and activity of PI3K were related to human inguinal hernia diseases. Additionally, others also show that inguinal hernia-related essential proteins, PTPN11, CDC42, and SOS1 regulate the RAS/MAPK signaling pathway, which is another downstream effector of RTKs [51][52][53][54]. Furthermore, essential proteins, PIK3R1 and TGFBR1 are involved in the regulation of both the PI3K/AKT and RAS/MAPK signaling pathways [55][56][57].…”

Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

“…SHP2 is one of the promoters involved in RAS activation. SHP2 is a necessary mediator of resistance upon receiving MEK blockade therapy, reported in pancreatic and lung cancers (Ruess et al, ) (Figure A). Adaptive resistance of cancer cells to MEK blockade therapy also occurs due to feedback RTK activation (Misale et al, ).…”

“…Activation of MEK (via phosphorylation) is induced by RAF isoforms, and its downstream target is ERK (Lu et al, ; Hazar‐Rethinam et al, ). Trametinib (Ablain et al, ), selumetinib (Ruess et al, ), and SL‐327 (Yan et al, ) are MEK inhibitors. Sensitivity to MEK inhibitors often occurs when there are mutations in upstream kinases.…”

Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma

“…These combination regimens have shown promising activity in preclinical models and are currently being evaluated in different clinical trials [63]. More recently, 3 studies provided compelling evidence suggesting that SHP2 inhibitors can overcome the adaptive response of KRAS -altered cancer cells to MEK inhibition [64,65,66]. These data pave the way for the clinical evaluation of combinations consisting of inhibitors of MEK and SHP2 for the treatment of KRAS -driven malignancies.…”

“…First, more than 90% of PDAC cases are driven by oncogenic mutations affecting KRAS . While direct targeting of oncogenically mutated KRAS is still in its infancy [54,55], several approaches to indirectly target oncogenic KRAS, including combined CHK1/MAPKAP-K2 inhibition, CHK1 inhibition in combination with genotoxic chemotherapy, combined MEK/PI3K or combined MEK/SHP2 inhibition, have recently emerged and await clinical validation [60,61,62,64,65,66,68,71]. Second, a sizable fraction of PDAC cases harbor germline mutations in a number of DNA repair genes, particularly those involved in DSB repair [13,14,15,16,17,18,19,20,21,22,23].…”