PTPN11 Plays Oncogenic Roles and Is a Therapeutic Target for BRAF Wild-Type Melanomas

Abstract

Melanoma is one of the most highly mutated cancer types. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in Kras, Erbb3, and Ptpn11. PTPN11 encodes the SHP2 protein tyrosine phosphatase that activates the RAS/RAF/MAPK pathway. Although PTPN11 is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in BRAF wild-type (either NRAS mutant or wild-type) melanoma cells. PTPN11 played oncogenic roles in melanoma by driving anchorage-independent colony formation and tumor growth. In Pten-and Cdkn2a-null mice, tet-inducible and melanocytespecific PTPN11 E76K expression significantly enhanced mela-noma tumorigenesis. Melanoma cells derived from this mouse model showed doxycycline-dependent tumor growth in nude mice. Silencing PTPN11 E76K expression by doxycycline withdrawal caused regression of established tumors by induction of apoptosis and senescence, and suppression of proliferation. Moreover, the PTPN11 inhibitor (SHP099) also caused regression of NRAS Q61K -mutant melanoma. Using a quantitative tyrosine phosphoproteomics approach, we identified GSK3a/ b as one of the key substrates that were differentially tyrosinephosphorylated in these experiments modulating PTPN11. This study demonstrates that PTPN11 plays oncogenic roles in melanoma and regulates RAS and GSK3b signaling pathways.Implications: This study identifies PTPN11 as an oncogenic driver and a novel and actionable therapeutic target for BRAF wild-type melanoma.

Downregulation of PTPN18 can inhibit proliferation and metastasis and promote apoptosis of endometrial cancer

“…Tissue‐based microarray expression analysis completed by Demirci Hakan et al have revealed that PTPN18 was differentially expressed in metastatic uveal melanoma in normal whole human blood and tissues prone to metastatic involvement by uveal melanoma. In another research about melanomas reported by Minjung Kim et al, PTPN11 was confirmed to play an oncogenic driver and a novel and actionable therapeutic target for BRAF wild‐type melanoma. Beicheng Sun et al suggested that PTPN12, PTPRN and PTPN18 were associated with the prognosis of hepatocellular carcinoma.…”

“…PTPN18 belongs to the PTPs that function as tumour suppressors or oncogenes in cancers . Tissue‐based microarray expression analysis completed by Demirci Hakan et al have revealed that PTPN18 was differentially expressed in metastatic uveal melanoma in normal whole human blood and tissues prone to metastatic involvement by uveal melanoma.…”

“…PTPN18 belongs to the PTPs that function as tumour suppressors or oncogenes in cancers. 12,13 Tissue-based microarray expression analysis completed by Demirci Hakan et al 14 hepatocellular carcinoma, 12 and recently, some associated analyses have gained attention and been added to the study of many diseases, such as cancers. 17,18 Previous linkage studies and exome sequencing analysis illustrated that a BDP1 mutation was associated with hereditary hearing loss.…”

Upregulated SHP‐2 expression in the epileptogenic zone of temporal lobe epilepsy and various effects of SHP099 treatment on a pilocarpine model

“…SHP099 was obtained from MedChem Express, USA (HY‐100388). SHP099 was dissolved in sterile saline and administered by oral gavage at 100 mg/kg daily . SHP099 concurrently binds to the interface of the N‐terminal SH2, C‐terminal SH2 and protein tyrosine phosphatase domains, thus inhibiting SHP‐2 activity through an allosteric mechanism .…”

Integrative analysis of large-scale loss-of-function screens identifies robust cancer-associated genetic interactions

“…For instance, many of the robust dependencies associated with the oncogene BRAF could be interpreted in terms of BRAF's role in the MAPK pathway. BRAF mutation was associated with increased sensitivity to inhibition of its downstream effectors MEK (MAP2K1) and ERK (MAPK1), and increased resistance to inhibition of the alternative RAF isoform gene CRAF (RAF1) and the MAPK regulator PTPN11 ( Figure 3A, 3B) 25 . BRAF mutation was also associated with increased sensitivity to inhibition of PEA15, presumably a result of the requirement of PEA15 for ERK dimerisation and signalling activity 26,27 .…”