See article by Maytin et al., p. 3026

Actinic keratoses (AK) are very common premalignant skin lesions (presquamous cell carcinoma) in patients with chronic sun damage. Recently, physicians have been empirically combining two treatment approaches, topical 5-fluorouracil (5FU) and photodynamic therapy (PDT), but without any scientific basis. In a mechanistic clinical study using surface fluorimetry and skin biopsies, Maytin and colleagues show that sequential 5FU and PDT improves AK clearance by upregulating mitochondrial heme enzymes, increasing target photosensitizer (protoporphyrin IX) expression, and increasing proapoptotic p53. The results provide a scientific rationale for combining two FDA-approved treatments in an effective, practical approach that reduces cutaneous precancer burden.

See article by Frank et al., p. 3087

Besides therapeutically targetable mutations in signal transduction pathways, mutations related to the KEAP1/NRF2-pathway are involved in malignant transformation in various cancers, including lung cancer. Based on the NGS-analysis of a large cohort of NSCLC patients, Frank and colleagues show that mutations in KEAP1 and NRF2 occurred nearly mutually exclusive even though strongly linked functionally. They are also associated with different histologies, clinical characteristics, and co-occurring molecular aberrations. Thus, patients with KEAP1- or NRF2-mutations are a heterogenous group. This work argues against a driver function of these mutations but suggests a pivotal role in chemotherapy resistance.

See article by Yang et al., p. 3097

Around 50% of non-small cell lung cancer (NSCLC) patients receiving first-generation EGFR inhibitors develop resistance by T790M mutation. Osimertinib has proven effective in overcoming T790M mutation; however, resistance inevitably develops. Yang and colleagues surveyed 416 cancer-related genes in 93 NSCLC patients who progressed on osimertinib by next-generation sequencing (NGS). EGFR mutation on G796/C797, L792 or L718/G719 residues were identified in approximately 1/3 of the patients; further, resistance mechanisms were functionally studied in vitro. In EGFR nonmutated patients, MET, KRAS, and PIK3CA mutations were discovered. This study uncovers novel osimertinib-resistant mechanisms using cell-free DNA-based liquid biopsy and provides grounds for future therapeutic strategies.

See article by Liu et al., p. 3186

Dysregulated zinc transport is involved in many malignancies, including pancreatic cancer, and it promotes tumor growth. To further understand the mechanism of zinc transporter-mediated cancer progression, Liu and colleagues used genetic inactivation and rescue assays in human pancreatic cancer cells and mouse models to demonstrate that a zinc importer ZIP4 promotes pancreatic cancer migration and invasion through decreasing ZO-1 and claudin-1 via activation of ZEB1, leading to upregulation of their targets FAK and Paxillin. These findings suggest a novel signaling pathway initiated by ZIP4 controlling pancreatic cancer invasiveness and metastasis, and may be a new therapeutic target for this devastating disease.