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A targeted therapy is one that has been developed to affect a specific target, such as an enzyme or receptor. Targeted therapies can either block or increase the function of their target in order to treat a given disease; in this case, cancer.
Aberrant signalling pathway activity is relevant for tumour growth and resistance to therapy, but remains hard to understand and target. Here, the authors develop VESPA, a phosphoproteomics-based machine learning algorithm that can elucidate response and adaptation to drug perturbations in cancer signalling pathways.
In a tumor-agnostic phase 2 basket trial, the oral FGFR1–FGFR3 inhibitor pemigatinib elicits responses in tumor types beyond cholangiocarcinoma and bladder cancer and in tumor types with rarer FGFR alterations, with insights provided into resistance mechanisms.
EBV (Epstein-Barr virus)-targeted therapy is limited by efficient agents inducing lytic cycle in cancer cells. Here they report a transcriptional activator incorporated into lipid nanoparticles that could specifically activate endogenous BZLF1 and induce lytic reactivation in EBV-positive cancer cells thereby suppress tumor progression.
Dias et al. have shown that intentional further activation of oncogenic signalling rather than its inhibition represents an alternative strategy leading to colorectal cancer cell death with tumour suppressive acquired resistance.
Effectively targeting deregulated KRAS signaling remains an unmet clinical need, as current approaches commonly lead to the development of chemoresistance in clinical settings. ADAM9-mediated lysosomal KRAS degradation is now shown to counteract PDAC chemoresistance independently of mutational status.
In this World View, H. Michael Shepard describes his personal story behind the discovery of trastuzumab, 25 years since its FDA approval for HER2-overexpressing breast cancers.