Platinum-based chemotherapy is the most common treatment in advanced-stage lung adenocarcinoma. Because the clinical significance of KRAS mutational status in this setting has not yet been clearly determined, a mutation subtype-specific analysis was performed in the so far largest cohort of Caucasian patients with KRAS mutant advanced-stage lung adenocarcinoma treated with platinum-based chemotherapy. 505 Caucasian stage III-IV lung adenocarcinoma patients with known amino acid substitution-specific KRAS mutational status and treated with platinum-based chemotherapy were included. The correlations of subtype-specific KRAS mutations with smoking status, progression-free and overall survival (PFS and OS, respectively) and therapeutic response were analysed. Among 338 KRAS wild-type, 147 codon 12 mutant and 20 codon 13 mutant patients, there were no mutation-related significant differences in PFS or OS (P values were 0.534 and 0.917, respectively). Eastern Cooperative Oncology Group (ECOG) status and clinical stage were significant independent prognostic factors. KRAS mutation showed a significant correlation with smoking status (P=0.018). Importantly, however, G12V KRAS mutant patients were significantly more frequent among never-smokers than all other codon 12 KRAS mutant (G12x) subtypes (P=0.016). Furthermore, this subgroup tended to have a higher response rate (66% versus 47%; P=0.077). A modestly longer median PFS was also found in the G12V mutant cohort (233days; versus 175days in the G12x group; P=0.145). While KRAS mutation status per se is neither prognostic nor predictive in stage III-IV lung adenocarcinoma, subtype-specific analysis may indeed identify clinically relevant subgroups of patients that may ultimately influence treatment decisions.

Oncogenic activation of the epidermal growth factor receptor (EGFR) signaling pathway occurs in a variety of tumor types, albeit in human melanoma, the contribution of EGFR is still unclear. The potential role of EGFR was analyzed in four BRAF-mutant, one NRAS-mutant and one wild-type NRAS-BRAF-carrying human melanoma cell lines. We have tested clinically available reversible tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, irreversible EGFR-TKI pelitinib and a reversible experimental compound PD153035 on in-vitro proliferation, apoptosis, migration as well as in-vivo metastatic colonization in a spleen-liver model. The presence of the intracellular domain of EGFR protein and its constitutive activity were demonstrated in all cell lines. Efficacies of EGFR-TKIs showed significant differences, and irreversible inhibition had the strongest antitumor potential. Compared with BRAF-mutant cells, wild-type BRAF was associated with relative resistance against gefitinib. In combination with gefitinib, selective mutant BRAF-inhibitor vemurafenib showed additive effect in all BRAF-mutant cell lines. Treatment of BRAF-mutant cells with gefitinib or pelitinib attenuated in-vitro cell migration and in-vivo colonization. Our preclinical data suggest that EGFR is a potential target in the therapy of BRAF-mutant malignant melanoma; however, more benefits could be expected from irreversible EGFR-TKIs and combined treatment settings.

Clinical evidence shows that following initial response to treatment, drug-resistant cancer cells frequently evolve and, eventually, most tumors become resistant to all available therapies. We compiled a focused library consisting of >500 commercially available or newly synthetized 8-hydroxyquinoline (8OHQ) derivatives whose toxicity is paradoxically increased rather than decreased by the activity of P-glycoprotein (Pgp), a transporter conferring multidrug resistance (MDR). Here, we deciphered the mechanism of action of NSC297366 that shows exceptionally strong Pgp-potentiated toxicity. Treatment of cells with NSC297366 resulted in changes associated with the activity of potent anticancer iron chelators. Strikingly, iron depletion was more pronounced in MDR cells due to the Pgp-mediated efflux of NSC297366–iron complexes. Our results indicate that iron homeostasis can be targeted by MDR-selective compounds for the selective elimination of multidrug resistant cancer cells, setting the stage for a therapeutic approach to fight transporter-mediated drug resistance. Significance: Modulation of the MDR phenotype has the potential to increase the efficacy of anticancer therapies. These findings show that the MDR transporter is a “double-edged sword” that can be turned against resistant cancer.

Cell type-dependent HIF1 -mediated effects of hypoxia on proliferation, migration and metastatic potential of human tumor cells Cell type-dependent HIF1 α-mediated effects of hypoxia on proliferation, migration and metastatic potential of human tumor cells