Selected Articles from This Issue

ARX788, a site-specific next-generation anti-HER2 ADC, employs an unnatural amino acid to conjugate cytotoxic drug with a highly stable oxime bond, resulting in superior stability and an extended half-life of 12.5 days in mice. In xenograft and PDX animal models, ARX788 demonstrates strong activity in breast and gastric tumors with both high HER2 and low HER2 expression levels. ARX788 is also highly effective in T-DM1 resistant PDX models. The encouraging preclinical data warrant further investigation of ARX788, which is currently in multi-regional clinical trials.

HRAS is exclusively dependent on farnesylation, a post-translational modification that is required for inserting the protein into the cell membrane and for aspects of signaling. Therefore, Gilardi and colleagues investigated the use of a farnesyltransferase inhibitor, tipifarnib, in restricting HRAS mutant cancer cells. Tipifarnib reduced MAPK signaling and generated cytostatic or cytotoxic responses in six HRAS mutant xenografts. Based on their findings, tipifarnib represents a candidate for precision therapy in head and neck squamous cell carcinoma patients harboring HRAS mutations.

Pan-PIM kinase inhibitors are studied in multiple human hematopoietic malignancies. Thus, understanding the mechanism of resistance to these agents is of clinical importance. Using Gene Set Enrichment Analysis of RNA-seq data and functional enrichment of network modules combined with reverse phase protein arrays, Lim and colleagues modeled PIM inhibitor resistance in early T-cell precursor acute lymphoblastic leukemia (ETP-ALL), a chemo-resistant subset of T-ALL. This analysis discloses that PIM inhibitor resistant cells contain an activated NF-κB pathway. Concurrent inhibition of NF-κB and PIM kinase overcomes this resistance and suppresses ETP-ALL growth, suggesting a potential drug combination approach to improve therap. of T-ALL patients.

Endogenous retroviruses (ERVs) and other long-terminal repeats (LTRs) make up approximately 8% of the genome, where they are occasionally transcribed as parts of other transcripts. As ERVs can serve as a source for immunogenicity, Topham and colleagues investigated the association of ERV levels with immunogenicity in metastatic breast, colorectal, and pancreatic cancers. They identified an ERV-associated viral mimicry phenotype in metastatic tumors. Although this phenotype did not associate with overall survival in their study, the phenotype did link to epigenetic dysregulation and immunogenicity. ERV levels are therefore a potential biomarker for immunotherapy responses in patients with metastatic tumors.