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Simple Summary Since it was first described over two decades ago, the Alternative Lengthening of Telomeres (ALT) pathway has been well accepted to hold clinical significance in cancer development, cancer diagnosis, and cancer treatment. In this review, first, we discuss how the activation of this pathway is determined. Then, we provide up-to-date statistics on the cancers ALT activity is detected in. We discuss the relationships between ALT positivity and prognosis as well as the pathogenetics of ALT positive cancers. Finally, we evaluate pre-clinical and clinical investigations of potential therapies targeting ALT. Abstract Many exciting advances in cancer-related telomere biology have been made in the past decade. Of these recent advances, great progress has also been made with respect to the Alternative Lengthening of Telomeres (ALT) pathway. Along with a better understanding of the molecular mechanism of this unique telomere maintenance pathway, many studies have also evaluated ALT activity in various cancer subtypes. We first briefly review and assess a variety of commonly used ALT biomarkers. Then, we provide both an update on ALT-positive (ALT+) tumor prevalence as well as a systematic clinical assessment of the presently studied ALT+ malignancies. Additionally, we discuss the pathogenetic alterations in ALT+ cancers, for example, the mutation status of ATRX and DAXX, and their correlations with the activation of the ALT pathway. Finally, we highlight important ALT+ clinical associations within each cancer subtype and subdivisions within, as well as their prognoses. We hope this alternative perspective will allow scientists, clinicians, and drug developers to have greater insight into the ALT cancers so that together, we may develop more efficacious treatments and improved management strategies to meet the urgent needs of cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) remains a particularly lethal disease that is resistant to targeted therapies. Tyrosine kinase inhibitors (TKIs), including erlotinib and gefitinib, which block the action of the human epidermal growth factor receptor type 1 receptor, provide small increases in patient survival when administered with gemcitabine. The retinoblastoma (Rb) tumor suppressor protein is an additional target in pancreatic cancer, due to its documented inactivation in PDAC. The present study, using cell number, apoptosis and immunoblotting assays, aimed to evaluate the effects of activation of the Rb tumor suppressor via dephosphorylation by small interfering RNA-mediated phosphatase activation. In the Panc1, MIAPaCa-2 and Capan-2 pancreatic cancer cell lines, and in normal H6c7 cells, the effects of phosphatase activation on Rb were revealed to be dependent on expression of the p16 tumor suppressor, which regulates Rb phosphorylation. Phosphatase activation had no effect on non-transformed pancreatic epithelial cells. When comparing kinase inhibition with phosphatase activation, it was demonstrated that kinase inhibition reduced proliferation, whereas phosphatase activation induced apoptosis. Both treatments together resulted in a greater reduction of pancreatic cancer cells than either treatment alone. In addition, the effects of combination treatment of phosphatase activation with TKIs on cell number and activation of the signal transducer and activator of transcription 3 (STAT3) resistance pathway were determined. The combination of Rb phosphatase activation with TKIs resulted in a greater reduction in cell number compared with either treatment alone, without STAT3 pathway activation. These data suggested that targeting Rb phosphorylation by activating phosphatase may be a rational strategy to inhibit pancreatic tumor cell growth, without activation of acquired resistance.