Broad-spectrum therapeutics in non-small cell lung cancer (NSCLC) are in demand. Most human solid tumors express proteoglycans modified with distinct oncofetal chondroitin sulfate (CS) chains that can be detected and targeted with recombinant VAR2CSA (rVAR2) proteins and rVAR2-derived therapeutics. Here, we investigated expression and targetability of oncofetal CS expression in human NSCLC. High oncofetal CS expression is associated with shorter disease-free survival and poor overall survival of clinically annotated stage I and II NSCLC patients (n = 493). Oncofetal CS qualifies as an independent prognosticator of NSCLC in males and smokers, and high oncofetal CS levels are more prevalent in EGFR/KRAS wild-type cases, as compared to mutation cases. NSCLC cell lines express oncofetal CS-modified proteoglycans that can be specifically detected and targeted by rVAR2 proteins in a CSA-dependent manner. Importantly, a novel VAR2-drug conjugate (VDC-MMAE) efficiently eliminates NSCLC cells in vitro and in vivo. In summary, oncofetal CS is a prognostic biomarker and an actionable glycosaminoglycan target in NSCLC.

Cisplatin is a widely used antineoplastic agent, whose efficacy is limited by primary and acquired therapeutic resistance. Recently, a bladder cancer genome-wide CRISPR/Cas9 knock-out screen correlated cisplatin sensitivity to multiple genetic biomarkers. Among the screen’s top hits was the HECT domain-containing ubiquitin E3 ligase (HUWE1). In this review, HUWE1 is postulated as a therapeutic response modulator, affecting the collision between platinum-DNA adducts and the replication fork, the primary cytotoxic action of platins. HUWE1 can alter the cytotoxic response to platins by targeting essential components of the DNA damage response including BRCA1, p53, and Mcl-1. Deficiency of HUWE1 could lead to enhanced DNA damage repair and a dysfunctional apoptotic apparatus, thereby inducing resistance to platins. Future research on the relationship between HUWE1 and platins could generate new mechanistic insights into therapy resistance. Ultimately, HUWE1 might serve as a clinical biomarker to tailor cancer treatment strategies, thereby improving cancer care and patient outcomes.