α-Amanitin Restrains Cancer Relapse from Drug-Tolerant Cell Subpopulations via TAF15

Abstract

Cancer relapse occurs with substantial frequency even after treatment with curative intent. Here we studied drug-tolerant colonies (DTCs), which are subpopulations of cancer cells that survive in the presence of drugs. Proteomic characterization of DTCs identified stemness- and epithelial-dominant subpopulations, but functional screening suggested that DTC formation was regulated at the transcriptional level independent from protein expression patterns. We consistently found that α-amanitin, an RNA polymerase II (RNAPII) inhibitor, effectively inhibited DTCs by suppressing TAF15 expression, which binds to RNA to modulate transcription and RNA processing. Sequential administration of α-amanitin and cisplatin extended overall survival in a cancer-relapse mouse model, namely peritonitis carcinomatosa. Therefore, post-treatment cancer relapse may occur through non-distinct subpopulations and may be effectively prevented by α-amanitin to disrupt transcriptional machinery, including TAF15.

Helicobacter pylori infection is associated with favorable outcome in advanced gastric cancer patients treated with S‐1 adjuvant chemotherapy

“…In previous studies we investigated gastric cancer cell lines exposed to anticancer agents as a model for assessing relapse suppression with adjuvant chemotherapy. 11,14 33 Our current study did not show clear associations with TP53 polymorphisms that reflect the 5-FU sensitivity observed in vitro, 11 which likely suggests that the treatment efficacy of adjuvant chemotherapy may predominantly involve a systemic response rather than the molecular response of cancer cells. 34,35 We hypothesize that once transformation occurs in a gastric mucosal cell, the proliferating cancer cells progress to an advanced stage regardless of H. pylori infection status, which is wellsupported by the "hit-and-run" model in H. pylori-associated carcinogenesis.…”

“…In previous studies we investigated gastric cancer cell lines exposed to anticancer agents as a model for assessing relapse suppression with adjuvant chemotherapy . The majority of adjuvant chemotherapy regimens use 5‐FU, which induces both p53 and NF‐κB to activate context‐specific transcriptional machinery in cancer cells in response to DNA damage .…”

“…30,31 Here, one of the challenging questions is whether H. pylori is associated with maintaining advanced gastric cancer. H. pylori has adapted to grow under strong acidic (14) conditions in the human stomach, 32 but some very advanced or relapsed forms of gastric cancer, such as peritoneal dissemination or liver metastasis, do not necessarily represent the acidic environment,…”

“…We previously identified aberrant nuclear expression of NF‐κB transcription factor and TP53 codon 72 polymorphisms, located in the NF‐κB binding site, as potential biomarkers for 5‐FU sensitivity based on a gastric cancer cell line model for post‐surgical patients treated with S‐1 adjuvant chemotherapy . However, target cells of the adjuvant therapy in patients are anchor‐free or micrometastatic, and therefore an assessment of anti‐tumor ability in vitro may not translate directly to the clinic . In addition, the occurrence of a systemic response to the chemotherapy in patients has not been fully considered .…”

Meeting key synthetic challenges in amanitin synthesis with a new cytotoxic analog: 5′-hydroxy-6′-deoxy-amanitin

“…2a Unlike other ADC payloads, a-amanitin targets both dividing and quiescent cells and shows potential for preventing cancer relapse from drug-tolerant cell subpopulations. 7 Examples include ADCs for targeting human epidermal growth factor receptor 2 and prostate specic membrane antigen. 8 With but a few exceptions, 9 nearly all bioconjugates to a cytotoxic amanitin have emerged from naturally-sourced a-amanitin.…”