ALK is a receptor tyrosine kinase, associated with many tumor types as diverse as anaplastic large cell lymphomas, inflammatory myofibroblastic tumors, breast and renal cell carcinomas, non-small cell lung cancer, neuroblastomas, and more. This makes ALK an attractive target for cancer therapy. Since ALK–driven tumors are dependent for their proliferation on the constitutively activated ALK kinase, a number of tyrosine kinase inhibitors have been developed to block tumor growth. While some inhibitors are under investigation in clinical trials, others are now approved for treatment, notably in ALK-positive lung cancer. Their efficacy is remarkable, however limited in time, as the tumors escape and become resistant to the treatment through different mechanisms. Hence, there is a pressing need to target ALK-dependent tumors by other therapeutic strategies, and possibly use them in combination with kinase inhibitors. In this review we will focus on the therapeutic potential of proapoptotic ALK-derived peptides based on the dependence receptor properties of ALK. We will also try to make a non-exhaustive list of several alternative treatments targeting ALK-dependent and independent signaling pathways.

Keratoconus (KC) is a multifactorial progressive ectatic disorder characterized by local thinning of the cornea, leading to decreased visual acuity due to irregular astigmatism and opacities. Despite the evolution of advanced imaging methods, the exact etiology of KC remains unknown. Our aim was to investigate the involvement of corneal epithelium in the pathophysiology of the disease. Corneal epithelial samples were collected from 23 controls and from 2 cohorts of patients with KC: 22 undergoing corneal crosslinking (early KC) and 6 patients before penetrating keratoplasty (advanced KC). The expression of genes involved in the epidermal terminal differentiation program and of the oxidative stress pathway was assessed by real time PCR analysis. Presence of some of the differentially expressed transcripts was confirmed at protein level using immunofluorescence on controls and advanced KC additional corneal samples. We found statistically significant under-expression in early KC samples of some genes known to be involved in the mechanical resistance of the epidermis (KRT16, KRT14, SPRR1A, SPRR2A, SPRR3, TGM1 and TGM5) and in oxidative stress pathways (NRF2, HMOX1 and HMOX2), as compared to controls. In advanced KC samples, expression of SPRR2A and HMOX1 was reduced. Decreased expression of keratin (KRT)16 and KRT14 proteins was observed. Moreover, differential localization was noted for involucrin, another protein involved in the epidermis mechanical properties. Finally, we observed an immunofluorescence staining for the active form of NRF2 in control epithelia that was reduced in KC epithelia. These results suggest a defect in the mechanical resistance and the oxidative stress defense possibly mediated via the NRF2 pathway in the corneal keratoconic epithelium.