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Most BRAF(V600E) mutant melanomas are sensitive to selective BRAF inhibitors, but BRAFmutant colon cancers are intrinsically resistant to these drugs because of feedback activation of EGFR. We performed an RNA-interference-based genetic screen in BRAFmutant 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 PTPN11blocks signaling from receptor tyrosine kinases (RTKs) to the RAS-MEK-ERK pathway. PTPN11suppression 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.

AbstractAs dual-specificity phosphatase (DUSP) expression has been correlated to sensitivity to MEK inhibitors, DUSP expression levels may indicate activation of the mitogen-activated protein kinase (MAPK) pathway in many tumor types. In this study, we investigate if DUSP levels can indicate different levels of MAPK activation within colorectal cancer (CRC) patients. In three different CRC patient microarray datasets, we analyzed the expression of DUSP1. DUSP4and DUSP6according to mutational status, their correlation with survival and their association with different clinical characteristics. DUSP4 was significantly differentially expressed between all mutational subgroups with the highest expression in BRAF mutated tumors. Moreover, high DUSP4 expression was associated with a worse overall survival and with clinical characteristics typical for BRAF mutant patients. The use of DUSP expression as a predictive biomarker towards MAPK targeted therapy in CRC patients needs further investigation.

This Review discusses recent evidence that indicates that different genetic alterations might be related to distinct sensitivity to targeted therapies. It examines prototypical examples and asks what is the role of cancer mutations as predictors of sensitivity and resistance to targeted therapies? Further, what are the implications for the 'personalized' treatment of cancer patients?

BACKGROUND Adjuvant chemoradiotherapy does not represent the standard of care in patients with resected high-risk gastric cancer; however, results from phase 2 and randomized trials suggest improvement in overall survival. We assessed the feasibility and toxic effects of chemoradiotherapy as adjuvant treatment in locally advanced gastric cancer. DESIGN Pilot study. SETTING University hospital. PATIENTS Twenty-nine patients with T4N+ or any TN23 gastric cancer previously treated with potentially curative surgery were enrolled. All of the patients received combined adjuvant chemotherapy with FOLFOX-4 (ie, a combination of folinic acid [leucovorin], fluorouracil, and oxaliplatin [Eloxatin]) for 8 cycles and concomitant radiotherapy (45 Gy in 25 daily fractions over 5 weeks). Radiotherapy was begun after the first 2 cycles of FOLFOX-4, which was reduced by 25% during the period of concomitant radiotherapy. MAIN OUTCOME MEASURES Treatment toxic effects according to the National Cancer Institute–Common Toxicity Criteria classification, overall and disease-free survival rates, and identification of prognostic indicators. RESULTS All of the patients completed treatment. Severe hematologic and gastrointestinal toxic effects occurred in 10% and 33%, respectively. No acute hepatic or renal toxic effects were observed; 1 patient experienced severe neurotoxicity. Disease-free and overall survival rates at 1, 2, and 3 years were 79%, 35%, and 35% and 85%, 62.6%, and 50.1%, respectively, and were shown to be substantially better than those observed in untreated patients. Long-term outcome was related to TNM stage, basal serum tumor marker level, and, particularly, lymph node ratio. CONCLUSION A multimodal approach with FOLFOX-4 and radiotherapy is feasible and effective for the treatment of patients with resected high-risk gastric cancer.Arch Surg. 2010;145(3):233-238--

Background: Gastric cancer still represents a leading cause of death worldwide. Several cytotoxic agents have demonstrated activity and combination regimens improve progression-free survival, overall survival and quality of life. Nevertheless, now there is no standard therapy for advanced gastric cancer patients. Objective: To evaluate the role of new investigational agents. Methods: We analysed Phase I, II and III studies that evaluated tailored drugs directed against the epidermal growth factor receptor (EGFR), the c-erbB2, the vascular endothelial growth factor (VEGF), the vascular endothelial growth factor receptor (VEGFR), the matrix metalloproteinases (MMP) and the mammalian target of rapamycin (mTOR). Conclusion: Data from Phase II trials indicate the potential of improved efficacy of chemotherapy when administered in combination with bevacizumab and cetuximab. Trastuzumab results are ongoing, while marimastat has not obtained clinical developments even if it has demonstrated to be an active drug in this setting of patients.