PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs

Abstract

Graphical Abstract Highlights d PTPN11 inhibition is synthetic lethal with BRAF inhibitors in BRAF mutant colon cancer d PTPN11 inhibition blocks the effects of EGFR activation by BRAF inhibitors d PTPN11 inhibition is lethal to cancers with activated RTKs d Phosphorylation of PTPN11 is a biomarker of RTK-driven drug resistance in melanoma Correspondence r.bernards@nki.nl In Brief Using a synthetic lethality screen, Prahallad et al. report that PTPN11 suppression enhances the response to BRAF inhibition in BRAF mutant colon cancers by preventing the effects of receptor tyrosine kinase reactivation. These findings identify PTPN11 as a drug target to combat both intrinsic and acquired resistance to targeted cancer drugs. SUMMARY Most BRAF (V600E) mutant melanomas are sensitive to selective BRAF inhibitors, but BRAF mutant colon cancers are intrinsically resistant to these drugs because of feedback activation of EGFR. We performed an RNA-interference-based genetic screen in BRAF mutant colon cancer cells to search for phosphatases whose knockdown induces sensitivity to BRAF inhibition. We found that suppression of protein tyrosine phosphatase non-receptor type 11 (PTPN11) confers sensitivity to BRAF inhibitors in colon cancer. Mechanistically, we found that inhibition of PTPN11 blocks signaling from receptor tyro-sine kinases (RTKs) to the RAS-MEK-ERK pathway. PTPN11 suppression is lethal to cells that are driven by activated RTKs and prevents acquired resistance to targeted cancer drugs that results from RTK activation. Our findings identify PTPN11 as a drug target to combat both intrinsic and acquired resistance to several targeted cancer drugs. Moreover, activated PTPN11 can serve as a biomarker of drug resistance resulting from RTK activation.

Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases

“…1, Fisher's exact P < 4.45 × 10 −14 ). These findings provide a robust crossvalidation of reports that RTK-driven cancer cells depend on SHP2 for survival 8,9 . Conversely, cell lines that were sensitive to KRAS, NRAS or BRAF depletion were refractory to SHP2 downregulation ( Fig.…”

SHP2 phosphatase as a novel therapeutic target for melanoma treatment

“…This is of particular interest since several of the currently proposed drug resistance mechanisms against melanoma, through upregulation of C-Raf [46], B-Raf [47], hepatocyte growth factor [48] or PDGFR [49], reactivate the signaling pathways which are mediated by SHP2. Indeed, a recent study indicates that SHP2 is a central node in intrinsic and acquired resistance to tyrosine kinase targeted cancer drugs [50]. However whether pharmacologic inhibition of SHP2 represents an effective approach for cancer therapy remains an outstanding question.…”

Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes

“…52 In addition, a Gly503Arg mutation in PTPN11, another gene of the RAS pathway that has been reported as being frequently mutated in RAS-opathies (juvenile myelomonocytic leukemia, adult acute myelogenous leukemia, gastric cancer, glioblastoma, and anaplastic large cell lymphoma) was identified. 36,37,53 This gene is thought to play a role in acquired resistance to targeted therapy 54 and therefore represents a potential drug target. PTPN11/SHP2 inhibitors have already been identified, and compounds are in preclinical testing.…”