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Page 886 Ojima. Cancer Drug Resist 2021;4:885-7 https://dx.doi.org/10.20517/cdr.2021.86

[2]
Venkatesh et al. presented an investigation into the redox properties of prostate-specific membrane
antigen (PSMA) receptors in the ligand trafficking endosomes, which are crucial for the design and
development of PSMA-targeted drug conjugates. Although there are different ways to implement drug
release mechanisms, disulfide bond reduction has been extensively employed to ensure intracellular drug
release in such ligand-based drug conjugates. Thus, the efficient receptor-targeted ligand-drug design must
understand the redox properties of endocytic compartments. This study has revealed that PMSA-targeted
ligand-drug probe is rapidly internalized by PSMA-positive cancer cells, but the release of the drug probe
stops at ~50% even after 24 h. This means that not all internalizing receptors are translocated through
similar intracellular compartments, and thus the efficiency of disulfide bond reduction must be
independently analyzed for each receptor trafficking pathway.

It has been shown that RAS oncogenes are the most commonly mutated oncogenes in human cancer, while
RAS-mutant cancers impose a heavy burden on human health. Although there have been some successes in
[3]
the inhibition of RAS effector signaling, targeting these mutations is very challenging. Conroy et al.
reviewed a newer approach, i.e., direct RAS inhibition, which has shown promising results in human
clinical trials. In this review, diverse approaches to RAS inhibition are summarized, and then the recent
successful developments in the direct inhibition of KRAS (G12C) with experimental drugs such as AMG510
(sotorasib), MRTX849 (Adagrasib), and BI-3406 are discussed.

Understanding the resistance mechanism is critically important in the discovery and development of
[4]
anticancer agents targeting cancer-specific signaling pathways. Bijnsdorp and Peters investigated
Rapamycin-resistance (mTOR signaling pathway) in human colon carcinoma cells and found that the drug
resistance is caused by thymidine-induced autophagy activation. The authors examined if thymidine
phosphorylase (TP) substrate thymidine and overexpression of TP affect mTOR signaling by comparing
Colo320 (TP-deficient) cells and its TP-transfected variant (Colo320TP1). The results clearly showed that
autophagy was highly induced by thymidine, which was decreased by the application of thymidine
phosphorylase inhibitor. Furthermore, the autophagy inhibitor 3-methyladenine completely inhibited
autophagy and its protection in Colo320TP1 cells.

The introduction of epidermal growth factor receptor (EGFR) gene tyrosine kinase inhibitors (TKIs) in
chemonaive patients with advanced non-small cell lung cancer (NSCLC) has dramatically improved the
progression-free survival compared to standard chemotherapy. However, the cost of treatment imposes a
challenge in the wide use of these targeted chemotherapeutics as the first-line drugs in the clinic. Giuliani
[5]
and Bonetti made a critical assessment of the pharmacological costs of TKIs (erlotinib, gefitinib, afatinib,
and osimertinib) in patients with activating EGFR mutations in first-line treatment for advanced NSCLC.
The authors concluded that osimertinib is most cost-effective based on incremental cost-effectiveness ratio,
but still, reducing costs is mandatory to consider osimertinib as the most cost-effective TKI in first-line
treatment.

In summary, this Special Issue includes review articles and original research articles, describing and
addressing some critical aspects of the tumor-targeting chemotherapy drugs in preclinical and clinical
studies.

DECLARATIONS
Authors’ contributions
The author contributed solely to the article.