Abstract:Acquired resistance to therapeutic drugs is a serious problem for patients with cancer receiving systemic treatment. Experimentally, drug resistance is established in cell lines by repeated, continuous exposure to escalating concentrations of the drug; however, the precise mechanism underlying the acquired resistance is not always known. Here, it is demonstrated that the human colorectal cancer cell line DLD1 with acquired resistance to trifluridine (FTD), a key component of the novel, orally administered nucl… Show more
“…S3). Furthermore, a recent study reported a similar finding in TK1 -knock-out DLD-1 cells 10 , suggesting that TK1 is essential for FTD cytotoxicity in a range of cell lines.Figure 1FTD cytotoxicity in TK1 -knock-out cells. ( A ) Schematic diagram of the TK1 locus on Chr17q25.3.…”
Trifluridine (FTD), a tri-fluorinated thymidine analogue, is a key component of the oral antitumor drug FTD/TPI (also known as TAS-102), which is used to treat refractory metastatic colorectal cancer. Thymidine kinase 1 (TK1) is thought to be important for the incorporation of FTD into DNA, resulting in DNA dysfunction and cytotoxicity. However, it remains unknown whether TK1 is essential for FTD incorporation into DNA and whether this event is affected by the expression level of TK1 because
TK1
-specific-deficient human cancer cell lines have not been established. Here, we generated
TK1
-knock-out human colorectal cancer cells using the CRISPR/Cas9 genome editing system and validated the specificity of
TK1
knock-out by measuring expression of
AFMID
, which is encoded on the same locus as
TK1
. Using
TK1
-knock-out cells, we confirmed that TK1 is essential for cellular sensitivity to FTD. Furthermore, we demonstrated a correlation between the
TK1
expression level and cytotoxicity of FTD using cells with inducible
TK1
expression, which were generated from
TK1
-knock-out cells. Based on our finding that the
TK1
expression level correlates with sensitivity to FTD, we suggest that FTD/TPI might efficiently treat cancers with high
TK1
expression.
“…S3). Furthermore, a recent study reported a similar finding in TK1 -knock-out DLD-1 cells 10 , suggesting that TK1 is essential for FTD cytotoxicity in a range of cell lines.Figure 1FTD cytotoxicity in TK1 -knock-out cells. ( A ) Schematic diagram of the TK1 locus on Chr17q25.3.…”
Trifluridine (FTD), a tri-fluorinated thymidine analogue, is a key component of the oral antitumor drug FTD/TPI (also known as TAS-102), which is used to treat refractory metastatic colorectal cancer. Thymidine kinase 1 (TK1) is thought to be important for the incorporation of FTD into DNA, resulting in DNA dysfunction and cytotoxicity. However, it remains unknown whether TK1 is essential for FTD incorporation into DNA and whether this event is affected by the expression level of TK1 because
TK1
-specific-deficient human cancer cell lines have not been established. Here, we generated
TK1
-knock-out human colorectal cancer cells using the CRISPR/Cas9 genome editing system and validated the specificity of
TK1
knock-out by measuring expression of
AFMID
, which is encoded on the same locus as
TK1
. Using
TK1
-knock-out cells, we confirmed that TK1 is essential for cellular sensitivity to FTD. Furthermore, we demonstrated a correlation between the
TK1
expression level and cytotoxicity of FTD using cells with inducible
TK1
expression, which were generated from
TK1
-knock-out cells. Based on our finding that the
TK1
expression level correlates with sensitivity to FTD, we suggest that FTD/TPI might efficiently treat cancers with high
TK1
expression.
“…HCT-116 cells were purchased from American Type Culture Collection in 2011. DLD1 cells were provided by Taiho Pharmaceutical Co. Ltd. (22). A549 cells were provided by Dr. M. Takeshita (Kyushu University) (21).…”
DNA replication stress is a predominant cause of genome instability, a driver of tumorigenesis and malignant progression. Nucleoside analog-type chemotherapeutic drugs introduce DNA damage and exacerbate DNA replication stress in tumor cells. However, the mechanisms underlying tumor cytotoxicity triggered by the drugs are not fully understood.Here, we show that the fluorinated thymidine analog trifluridine (FTD), an active component of the chemotherapeutic drug trifluridine/tipiracil, delayed DNA synthesis by human replicative DNA polymerases. FTD acted as an inefficient deoxyribonucleotide triphosphate source (FTD triphosphate) and as an obstacle base (trifluorothymine) in the template DNA strand. At the cellular level, FTD decreased thymidine triphosphate in the dNTP pool and induced FTD triphosphate accumulation, resulting in replication fork stalling caused by FTD incorporation into DNA. DNA lesions involving single-stranded DNA were generated as a result of replication fork stalling, and the p53-p21 pathway was activated. Although FTD suppressed tumor cell growth irrespective of p53 status, tumor cell fate diverged at the G2/M phase transition according to p53 status; tumor cells with wild-type p53 underwent cellular senescence via mitosis skip, whereas tumor cells that lost wild-type p53 underwent apoptotic cell death via aberrant late mitosis with severely impaired separation of sister chromatids.These results suggest that DNA replication stress induced by a nucleoside analog-type chemotherapeutic drug triggers tumor cytotoxicity by determining tumor cell fate according to p53 status.Significance: This study identified a unique type of DNA replication stress induced by trifluridine, which directs tumor cell fate either toward cellular senescence or apoptotic cell death according to p53 status.
“…The treatment sequence is an important element of our trial 4 . We previously showed that 5‐FU‐based chemotherapy is effective even in tumors becoming refractory to FTD after trifluridine/tipiracil treatment 22 . Since FTD/TPI does not have cross‐resistance with 5‐fluorouracil, 10,13,23 capecitabine/Bev can be selected as a subsequent therapy.…”
Background
A previous Phase I/II study demonstrated that TAS‐102 (trifluridine/tipiracil [FTD/TPI]) plus bevacizumab (Bev) has encouraging efficacy and controllable safety for patients with previously treated metastatic colorectal cancer. Therefore, we designed for assessing the efficacy and safety of FTD/TPI plus Bev in elderly patients with previously untreated metastatic colorectal cancer.
Methods
This is a multicenter, single‐arm Phase II study included patients ≥70 years old with previously untreated, unresectable metastatic colorectal cancer. Treatment consisted of FTD/TPI plus Bev given every 4 weeks. The primary endpoint was progression‐free survival (PFS), assuming a null hypothesis of a PFS of 5 months. The secondary endpoints were the overall survival (OS), overall response rate (ORR), and adverse events (AEs).
Results
Between 5 January 2017 and 13 March 2018, 39 patients were enrolled from 18 institutions. The median patient age was 76.0 years (range, 70–88); the ECOG‐PS was 0 in 24 patients and 1 in 15 patients. The median PFS was 9.4 months as a primary endpoint, and the median OS was 22.4 months. The ORR was 40.5% and the disease control rate was 86.5%. Grade 3–4 AEs included neutropenia (71.8%), leukopenia (51.3%), anorexia (15.4%), febrile neutropenia (10.3%), and fatigue (10.3%).
Conclusions
FTD/TPI plus Bev is an effective and well‐tolerated regimen for elderly patients with previously untreated metastatic colorectal cancer. Capecitabine/bevacizumab can be selected as a subsequent maintenance therapy without irinotecan and oxaliplatin because FTD/TPI has no cross‐resistance with 5‐fluorouracil.
Clinical trial registration: UMIN clinical trials registry (UMIN000025241).
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