Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue.

A missense C1858T single nucleotide polymorphism in the PTPN22 gene recently emerged as a major risk factor for human autoimmunity. PTPN22 encodes the lymphoid tyrosine phosphatase (LYP), which forms a complex with the kinase Csk and is a critical negative regulator of signaling through the T cell receptor. The C1858T single nucleotide polymorphism results in the LYP-R620W variation within the LYP-Csk interaction motif. LYP-W620 exhibits a greatly reduced interaction with Csk and is a gain-of-function inhibitor of signaling. Here we show that LYP constitutively interacts with its substrate Lck in a Csk-dependent manner. T cell receptor-induced phosphorylation of LYP by Lck on an inhibitory tyrosine residue releases tonic inhibition of signaling by LYP. The R620W variation disrupts the interaction between Lck and LYP, leading to reduced phosphorylation of LYP, which ultimately contributes to gain-of-function inhibition of T cell signaling.

A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas.

Sarcomas comprise a large heterogeneous group of mesenchymal cancers with limited therapeutic options. When treated with standard cytotoxic chemotherapies, many sarcomas fail to respond completely and rapidly become treatment resistant. A major problem in the investigation and treatment of sarcomas is the fact that no single gene mutation or alteration has been identified among the diverse histologic subtypes. We searched for therapeutically druggable targets that are common to a wide range of histologies and hence could provide alternatives to the conventional chemotherapy. Seven hundred samples comprising 45 separate histologies were examined. We found that almost 90% were arginine auxotrophs, as the expression of argininosuccinate synthetase 1 was lost or significantly reduced. Arginine auxotrophy confers sensitivity to arginine deprivation, leading temporarily to starvation and ultimately to cell survival or death under different circumstances. We showed that, in sarcoma, arginine deprivation therapy with pegylated arginine deiminase (ADI-PEG20) maintains a prolonged state of arginine starvation without causing cell death. However, when starvation was simultaneously prolonged by ADI-PEG20 while inhibited by the clinically available drug chloroquine, sarcoma cells died via necroptosis and apoptosis. These results have revealed a novel metabolic vulnerability in sarcomas and provided the basis for a well-tolerated alternative treatment strategy, potentially applicable to up to 90% of the tumors, regardless of histology.

Risk-stratified patients with resectable soft tissue sarcoma benefit from epirubicin-based adjuvant chemotherapy.

As adjuvant chemotherapy (AC) for soft tissue sarcomas is controversial, we performed a retrospective analysis of patients seen at Washington University in St. Louis to evaluate whether it benefited our patient population. Patients were risk-assessed using the Memorial Sloan Kettering Predictive Nomogram (MSKPN). We defined high-risk patients by a MSKPN 4-year postoperative probability of sarcoma-specific death of ≥0.3 and investigated if they benefited from AC. Retrospective review was performed on patients seen between 15 February 1996 and 6 February 2010. A propensity score method in the logistic regression framework was used to model the likelihood of receiving AC. To make causal inference on the effect of AC on survival outcomes, a propensity score inverse probability of treatment weighting approach was applied to survival analysis. Overall, 135 high-grade patients were assessed, 33 were treated with Ifosfamide/Epirubicin (I/Epi) and 102 were non AC patients. The stratified MSKPN risk was not significantly associated with any survival endpoint in the whole cohort, but trended for overall survival (OS) when evaluated against non AC patients. After adjustment for MSKPN risk and other variables, patients not receiving chemotherapy had significantly worse OS, recurrent free survival, and disease-specific survival (DSS) with adjusted hazard ratios of 4.18 (95% CI: 2.22-7.90), 8.96 (95% CI: 3.85-20.83), and 5.42 (95% CI: 2.09-14.06), respectively. In retrospective analyses, risk-stratified patients with soft tissue sarcoma benefited from I/Epi-based AC. Randomized I/Epi versus I/Doxorubicin clinical trials may determine the optimal adjuvant treatment.