Activation of CD44/PAK1/AKT signaling promotes resistance to FGFR1 inhibition in squamous-cell lung cancer

Lung cancer is the leading cause of cancer-related deaths worldwide. Fibroblast growth factor receptor 1 (FGFR1) gene amplification is one of the most prominent and potentially targetable genetic alterations in squamous-cell lung cancer (SQCLC). Highly selective tyrosine kinase inhibitors have been developed to target FGFR1; however, resistance mechanisms originally existing in patients or acquired during treatment have so far led to limited treatment efficiency in clinical trials. In this study we performed a wide-scale phosphoproteomic mass-spectrometry analysis to explore signaling pathways that lead to resistance toward FGFR1 inhibition in lung cancer cells that display (i) intrinsic, (ii) pharmacologically induced and (iii) mutationally induced resistance. Additionally, we correlated AKT activation to CD44 expression in 175 lung cancer patient samples. We identified a CD44/PAK1/AKT signaling axis as a commonly occurring resistance mechanism to FGFR1 inhibition in lung cancer. Co-inhibition of AKT/FGFR1, CD44/FGFR1 or PAK1/FGFR1 sensitized ‘intrinsically resistant’ and ‘induced-resistant’ lung-cancer cells synergetically to FGFR1 inhibition. Furthermore, strong CD44 expression was significantly correlated with AKT activation in SQCLC patients. Collectively, our phosphoproteomic analysis of lung-cancer cells resistant to FGFR1 inhibitor provides a large data library of resistance-associated phosphorylation patterns and leads to the proposal of a common resistance pathway comprising CD44, PAK1 and AKT activation. Examination of CD44/PAK1/AKT activation could help to predict response to FGFR1 inhibition. Moreover, combination between AKT and FGFR1 inhibitors may pave the way for an effective therapy of patients with treatment-resistant FGFR1-dependent lung cancer

Enhancer of Zeste Homolog 2 (EZH2) Is a Marker of High-Grade Neuroendocrine Neoplasia in Gastroenteropancreatic and Pulmonary Tract and Predicts Poor Prognosis

Tumor grading is a robust prognostic predictor in patients with neuroendocrine neoplasms (NEN) and guides therapy, especially in tumors with high proliferation. NEN can be separated into well-differentiated and poorly differentiated types. The more aggressive NEN have been further separated into neuroendocrine tumors (NET G3) with a better prognosis and neuroendocrine carcinomas (NEC) with a worse prognosis. Despite this distinction’s tremendous clinical and therapeutic relevance, optimal diagnostic biomarkers are still lacking. In this study, we analyzed the protein expression and prognostic impact of Enhancer of Zeste Homolog 2 (EZH2) by immunohistochemistry in 219 tissue samples of gastroenteropancreatic (GEP-NEN) and pulmonary NEN (P-NEN). EZH2 was almost exclusively expressed in NEN with a proliferation rate above 20% (G3), while all low-grade tumors were nearly negative. Among high-grade NEN, 65% showed high and 35% low expression of EZH2. In this group, the high expression of EZH2 was significantly associated with poor overall survival and NEC histology. Interestingly, EZH2 seems to act independently of Polycomb Repressive Complex 2 (PRC2) in NEN. In conclusion, we propose EZH2 as a robust biomarker for distinguishing between NET G3 and NEC among gastroenteropancreatic and pulmonary NEN

Selective Inactivation of Cancer Drugs by SAMHD1 Provides a Molecular Rationale for Therapeutic Stratification in AML

Background: Nucleoside analog (NA) drugs are widely used to treat a variety of cancers, including acute myeloid leukemia (AML). With an essential role in regulating the cellular dNTP pool by degrading cellular nucleotides, SAMHD1 has the potential to decrease the cellular concentration of frequently prescribed NAs and thereby diminish their clinical efficacy in cancer therapy. Method: In this study, we used biochemical, structural, and cell based methods to examine the interaction of SAMHD1 with various AML cancer drugs, including cytarabine, cladribine, clofarabine, fludarabine, gemcitabine and the two DNA-hypomethylating agents (HMAs) decitabine and azacytidine. Results: We found that both the catalytic and the allosteric sites of SAMHD1 can bind NAs and that the SAMHD1 substrate specificity is regulated by 2′ sugar modifications of the nucleotide analogs. Cell culture, AML blasts and xenotransplantation models confirmed the crystallography findings that most of these drugs are affected by SAMHD1 activity, while some stay unaffected. In accordance with these data expression levels of SAMHD1 are correlating with survival parameters in patients treated with SAMHD1-dependent NAs. Conclusion: Taken together, these results establish SAMHD1 as a substrate-specific resistance factor that has promise as a predictive biomarker for drug stratification and a therapeutic target in nucleoside analog-based AML therapy. Conflict of interest: non