RAS-MAPK in ALK targeted therapy resistance

The clinical success of ALK targeted therapy is limited by resistance. To identify rational co-targeting strategies to enhance clinical outcomes, we explored the molecular basis of ALK oncogene dependence in ALK gene rearrangement positive (ALK+) lung adenocarcinoma. We discovered that the RAS-RAF-MEK-ERK pathway is the critical downstream pathway necessary for ALK+ tumor cell survival. Upfront co-targeting of ALK plus MEK enhanced response and forestalled resistance in preclinical ALK+ tumor models, providing rationale for a new approach the treatment of ALK+ patients

Adaptive stress signaling in targeted cancer therapy resistance

© 2015 Macmillan Publishers Limited The identification of specific genetic alterations that drive the initiation and progression of cancer and the development of targeted drugs that act against these driver alterations has revolutionized the treatment of

Complex II specific dissociation links pH changes to oxidative stress for apoptosis induction

National audienc

Complex II specific dissociation links pH changes to oxidative stress for apoptosis induction

National audienc

Stefan Grimm, 1963-2014, a tragic loss for the scientific community Obituary

International audienc

The anticancer gene ORCTL3 targets stearoyl-CoA desaturase-1 for tumour-specific apoptosis

ORCTL3 is a member of a group of genes, the so-called anticancer genes, that cause tumour-specific cell death. We show that this activity is triggered in isogenic renal cells upon their transformation independently of the cells' proliferation status. For its cell death effect ORCTL3 targets the enzyme stearoyl-CoA desaturase-1 (SCD1) in fatty acid metabolism. This is caused by transmembrane domains 3 and 4, which are more efficacious in vitro than a low molecular weight drug against SCD1, and critically depend on their expression level. SCD1 is found upregulated upon renal cell transformation indicating that its activity, while not impacting proliferation, represents a critical bottleneck for tumourigenesis. An adenovirus expressing ORCTL3 leads to growth inhibition of renal tumours in vivo and to substantial destruction of patients' kidney tumour cells ex vivo. Our results indicate fatty acid metabolism as a target for tumour-specific apoptosis in renal tumours and suggest ORCTL3 as a means to accomplish this. </p