Highlights of This Issue

Platinum-based chemotherapy remains the standard of care in many cancer types; however, responses vary dramatically and many patients suffer from the side-effects with no tumor regression. Leung and colleagues demonstrate in multiple in vivo model systems that suppression of PAPSS1 (a gene necessary for sulfonation reactions) enhances sensitivity to cisplatin in non-small cell lung cancer. Furthermore, lung and ovarian cancer patients with low PAPSS1 expression have better overall survival following platinum-based chemotherapy. As such, PAPSS1 may serve as a predictive marker for treatment response to platins and an inhibitor against PAPSS1 may be useful in improving treatment outcomes.

Minimally invasive diagnosis of endometrial cancer (EC) is based on the histological examination of cells contained in uterine aspirates. This procedure, however, presents limitations to diagnose patients and to assign the correct tumor histotype and grade in 22% and 50% of cases, respectively. Martinez-Garcia and colleagues identify a 2-protein panel that can accurately detect EC among women entering the diagnostic process (AUC: 0.96), and a 3-protein panel that allows for the accurate discrimination of EC histological types (AUC: 0.99). These molecular signatures are aimed to preclude invasive diagnosis and help to predict the optimal surgical treatment for EC patients.

Development of acquired resistance to AZD9291, an approved 3^rd generation EGFR inhibitor for treatment of EGFR-mutant non-small cell lung cancer with T790M mutation has become a major obstacle in the clinic for a long-term efficacy. Shi and colleagues demonstrate a critical role of modulation of MEK/ERK-dependent Bim and Mcl-1 degradation in mediating sensitivity and resistance of cancer cells to AZD9291, providing a strong scientific rationale for the clinical investigation of the combination of AZD9219 with a MEK inhibitor as a strategy to overcome acquired resistance to AZD9291 or other third-generation EGFR inhibitors.

METex14 del mutations represent a novel class of driver mutations. Multiple MET inhibitors have demonstrated evidence of clinical activity in this molecularly defined subset of NSCLC. Nonclinical and clinical evidence of resistance due to MET A-loop mutations is emerging. Engstrom and colleagues explored mechanisms of resistance to different classes of MET inhibitors and found that glesatinib, a type II MET inhibitor, exhibited activity against clinically relevant acquired resistance mutations. Glesatinib demonstrated evidence activity in both nonclinical resistance models and patients supporting its utility in combatting drug resistance and enabling sequential treatment strategies.