Synthetic Lethality with Trifluridine/Tipiracil and Checkpoint Kinase 1 Inhibitor for Esophageal Squamous Cell Carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) is a disease characterized by a high mutation rate of the TP53 gene, which plays pivotal roles in the DNA damage response (DDR) and is regulated by checkpoint kinase (CHK) 2. CHK1 is another key DDR-related protein, and its selective inhibition is suggested to be particularly sensitive to TP53-mutated cancers, because a loss of both pathways (CHK1 and/or CHK2-p53) is lethal due to the serious impairment of DDR. Such a therapeutic strategy is termed synthetic lethality. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and prexasertib (CHK1 inhibitor) as a treatment for ESCC. Trifluridine is a key component of the antitumor drug combination with trifluridine/tipiracil (an inhibitor of trifluridine degradation), also known as TAS-102. In this study, we demonstrate that trifluridine increases CHK1 phosphorylation in ESCC cells combined with a reduction of the S-phase ratio as well as the induction of ssDNA damage. Because CHK1 phosphorylation is considered to be induced as DDR for trifluridine-mediated DNA damage, we examined the effects of CHK1 inhibition on trifluridine treatment. Consequently, CHK1 inhibition by short hairpin RNA or treatment with the CHK1 inhibitor, prexasertib, markedly enhanced trifluridine-mediated DNA damage, represented by an increase of gH2AX expression. Moreover, the combination of trifluridine/tipiracil and CHK1 inhibition significantly suppressed tumor growth of ESCC-derived xenograft tumors. Furthermore, the combination of trifluridine and prexasertib enhanced radiosensitivity both in vitro and in vivo. Thus, the combination of trifluridine/tipiracil and a CHK1 inhibitor exhibits effective antitumor effects, suggesting a novel therapeutic strategy for ESCC.

Comparative genomic analysis of esophageal squamous cell carcinoma and adenocarcinoma: New opportunities towards molecularly targeted therapy

“…WEE1 inhibitor AZD1775 in combination with chemotherapy showed superior response rate in TP53 mutated patients (21%) compared with those with wild-type TP53 (12%) 97 . Combination DNA damage response inhibitors such as inhibitors targeting ATR, CHK1/2 with chemotherapy/radiotherapy also displayed potential for the treatment of esophageal cancer 98 . The combination of an ATR inhibitor, elimusertib, or a WEE1 inhibitor, adavosertib, with chemotherapy/radiotherapy for the treatment of advanced solid tumors including esophageal carcinoma is being tested in clinical trials ( Fig.…”

Multicenter phase II study of trifluridine/tipiracil for esophageal squamous carcinoma refractory/intolerant to 5-fluorouracil, platinum compounds, and taxanes: the ECTAS study

“…Although this study failed to show the activity of FTD/TPI in heavily treated esophageal cancer, its good tolerability would provide us with the possibility of a new treatment combination of FTD/TPI with other chemotherapeutics after the failure of immune checkpoint inhibitors. Recently, our group found a promising effect of FTD/TPI / CHK1 inhibitor in a preclinical study [23], based on the concept that loss of two DNA damage response pathways (ATR-CHK1-WEE1 and ATM-CHK2-P53) induces synthetic lethality. Further research is required to better elucidate the combinations that may provide clinical benefits with FTD/TPI in ESCC patients.…”

HER2 G776S mutation promotes oncogenic potential in colorectal cancer cells when accompanied by loss of APC function

“…The total cell lysate was extracted with lysis buffer, which is a mixture of RIPA buffer (Nacalai Tesque) and PhosSTOP phosphatase inhibitor (Sigma-Aldrich, St. Louis, MO). Western blot analysis was performed as described previously 39 . The antibodies and enhanced chemiluminescence solution are described in Supplementary Table 6 .…”