Significance of thymidylate synthase for resistance to pemetrexed in lung cancer

Ozasa, Hiroaki; Oguri, Tetsuya; Uemura, Takashi; Miyazaki, Mikinori; Maeno, Ken; Sato, Shigeki; Ueda, Ryuzo

doi:10.1111/j.1349-7006.2009.01358.x

Cited by 103 publications

(86 citation statements)

References 24 publications

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“…Pemetrexed sensitivity has also been suggested to correlate inversely with TS expression in human cancer (26,27). Several preclinical studies also support such an inverse relation between TS expression and sensitivity to TS-targeted agents, likely reflecting the role of TS as a target for these drugs (28)(29)(30)(31). These observations support the notion that BIBW2992-induced downregulation of TS underlies, at least in part, the enhanced antitumor effect of combination therapy with either S-1 or pemetrexed.…”

Section: Discussionsupporting

confidence: 72%

Enhanced Anticancer Effect of the Combination of BIBW2992 and Thymidylate Synthase–Targeted Agents in Non–Small Cell Lung Cancer with the T790M Mutation of Epidermal Growth Factor Receptor

Takezawa

Okamoto

Tanizaki

et al. 2010

Molecular Cancer Therapeutics

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Most non-small cell lung cancer (NSCLC) tumors with activating mutations of the epidermal growth factor receptor (EGFR) are initially responsive to first-generation, reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib, but they subsequently develop resistance to these drugs through either acquisition of an additional T790M mutation of EGFR or amplification of the proto-oncogene MET. We have now investigated the effects of combination treatment with thymidylate synthase (TS)-targeting drugs and the secondgeneration, irreversible EGFR-TKI BIBW2992 on the growth of NSCLC cells with the T790M mutation. The effects of BIBW2992 on EGFR signaling and TS expression in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of BIBW2992 and the TS-targeting agents S-1 (or 5-fluorouracil) or pemetrexed on the growth of gefitinib-resistant NSCLC cells were examined both in vitro and in vivo. The combination of BIBW2992 with 5-fluorouracil or pemetrexed synergistically inhibited the proliferation of NSCLC cells with the T790M mutation in vitro, whereas an antagonistic interaction was apparent in this regard between gefitinib and either of these TS-targeting agents. BIBW2992 induced downregulation of TS in the gefitinib-resistant NSCLC cells, implicating depletion of TS in the enhanced antitumor effect of the combination therapy. The combination of BIBW2992 and either the oral fluoropyrimidine S-1 or pemetrexed also inhibited the growth of NSCLC xenografts with the T790M mutation to an extent greater than that apparent with either agent alone. The addition of TS-targeting drugs to BIBW2992 is a promising strategy to overcome EGFR-TKI resistance in NSCLC with the T790M mutation of EGFR. Mol Cancer Ther; 9(6); 1647-56. ©2010 AACR.

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Section: Discussionsupporting

confidence: 72%

Enhanced Anticancer Effect of the Combination of BIBW2992 and Thymidylate Synthase–Targeted Agents in Non–Small Cell Lung Cancer with the T790M Mutation of Epidermal Growth Factor Receptor

Takezawa

Okamoto

Tanizaki

et al. 2010

Molecular Cancer Therapeutics

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“…22,23 Selection of chemotherapeutic agents is also targeted, and pemetrexed has been shown to be more effective in adenocarcinomas than squamous cell carcinomas, and it is believed that this is dependent on the levels of thymidylate synthase expression. [16][17][18] Unfortunately, although more options now exist for patients with non-small cell lung cancer, mixed histology tumors such as adenosquamous carcinomas have not yet been extensively studied, and no clear treatment protocols exist. This is especially disconcerting, as adenosquamous carcinomas have been shown to have poorer prognosis than adenocarcinomas and squamous cell carcinomas in many studies, 4,5 including Takamori et al 24 of 56 adenosquamous carcinomas, 1 of the largest adenosquamous series, in which they compared Kaplan-Meier survival curves of these three different types of non-small cell lung cancer.…”

Section: Discussionmentioning

confidence: 99%

“…14 Squamous cell carcinomas are known to have higher levels of thymidylate synthase expression than adenocarcinomas, 15 and it is speculated that the efficacy of pemetrexed partially depends upon the level of thymidylate synthase expression. [16][17][18] Accordingly, pemetrexed is approved solely for the treatment of patients with non-squamous tumors for whom it is viewed as a superior drug as compared with taxanes or gemcitabine based on the above data.…”

mentioning

confidence: 99%

Thymidylate synthase expression and molecular alterations in adenosquamous carcinoma of the lung

et al. 2013

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Thymidylate synthase expression is known to be higher in squamous cell carcinoma than in adenocarcinoma of the lung. It is thought that this is the reason for the poor efficacy of pemetrexed in squamous cell carcinoma. However, there is limited data on thymidylate synthase expression in adenosquamous carcinoma, a distinct subtype of lung cancer containing both squamous and glandular differentiation. Furthermore, molecular alterations like epidermal growth factor receptor and Kirsten rat sarcoma 2 viral oncogene homolog mutations, which are seen in adenocarcinomas, are not well understood in mixed histology tumors such as adenosquamous carcinoma. In our study, we sought to better characterize adenosquamous tumors of the lung. Using immunohistochemistry to evaluate thymidylate synthase protein levels, we found that the expression of thymidylate synthase in these mixed tumors roughly parallel that of squamous cell carcinoma, instead of falling in between squamous cell and adenocarcinoma. Of note, in adenosquamous samples, the expression of thymidylate synthase was more closely correlated within the two components than would be expected by random chance alone. Also, we had a relatively high rate of epidermal growth factor receptor (11%) and Kirsten rat sarcoma 2 viral oncogene homolog (33%) mutations in these specimens, with the mutations showing convergence in both the glandular and squamous components upon microdissection. Our results indicate that adenosquamous carcinomas are not simple mixtures of their two histological components; they rather behave as their own entity, and it is important to further understand their behavior. Given the similarity of thymidylate synthase expression between squamous cell and adenosquamous carcinoma, and that thymidylate synthase is the main target of pemetrexed, we extrapolate that pemetrexed may also have inferior clinical activity in adenosquamous carcinoma.

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“…A number of mechanisms, including a high TS expression level, have been reported in association with resistance to 5-FU and its derivatives (7)(8)(9)(10)(11). Clinical investigations suggest a survival advantage for TS-targeting agents in patients with non-squamous cell carcinoma (12)(13).…”

Section: Discussionmentioning

confidence: 99%

S-1 monotherapy for previously treated non-small cell lung cancer: A retrospective analysis by age and histopathological type

et al. 2011

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Abstract. S-1, an oral fluoropyrimidine derivative, has been approved for the treatment of non-small cell lung cancer (NSCLC) in Japan. In the present study, the efficacy and safety of S-1 monotherapy for elderly patients with previously treated NSCLC were retrospectively evaluated, and the efficacy of S-1 monotherapy was compared by histopathological type. This retrospective study included 54 patients with advanced or recurrent NSCLC who had received S-1 monotherapy following the failure of previous chemotherapy regimens at our institutes. Patient outcomes were compared based on their age and histopathological type. S-1 was administered orally, twice daily, while the duration and interval were modified according to the medical condition of each patient. The default delivery schedule, the mean number of S-1 cycles, did not differ significantly between the two age groups (<70 and ≥70 years). The rate of therapy discontinuation, schedule modification or dose reduction due to intolerable toxicities or patient refusal was relatively frequent in the older group (40.7 and 55.6% for ages <70 and ≥70 years, respectively; p= 0.414), and the incidence of grade 3 anemia was relatively high in the older group (3.7 and 18.5%, respectively; p=0.192). The response rates (13.0 and 4.8%, respectively; p= 0.609) and disease control rates (39.1 and 33.3%, respectively; p= 0.761) did not differ significantly between the two age groups. According to histopathological type, the disease control rate was significantly higher in adenocarcinoma (57.9%) compared to non-adenocarcinoma (20.0%, p=0.013). Thus, S-1 monotherapy may be equally effective and tolerated in patients <70 years and those ≥70 years. Additionally, adenocarcinoma may have a higher disease control rate than non-adenocarcinoma.

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Significance of thymidylate synthase for resistance to pemetrexed in lung cancer

Cited by 103 publications

References 24 publications

Enhanced Anticancer Effect of the Combination of BIBW2992 and Thymidylate Synthase–Targeted Agents in Non–Small Cell Lung Cancer with the T790M Mutation of Epidermal Growth Factor Receptor

Enhanced Anticancer Effect of the Combination of BIBW2992 and Thymidylate Synthase–Targeted Agents in Non–Small Cell Lung Cancer with the T790M Mutation of Epidermal Growth Factor Receptor

Thymidylate synthase expression and molecular alterations in adenosquamous carcinoma of the lung

S-1 monotherapy for previously treated non-small cell lung cancer: A retrospective analysis by age and histopathological type

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