Crizotinib for recurring non‐small‐cell lung cancer with <scp><i>EML4‐ALK</i></scp> fusion genes previously treated with alectinib: A phase <scp>II</scp> trial

Harada, Daijiro; Isozaki, Hideko; Kozuki, Toshiyuki; Yokoyama, Toshihide; Yoshioka, Hiroshige; Bessho, Akihiro; Hosokawa, Shinobu; Takata, Ichiro; Takigawa, Nagio; Hotta, Katsuyuki; Kiura, Katsuyuki

doi:10.1111/1759-7714.13825

Cited by 8 publications

(8 citation statements)

References 30 publications

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“…After oral administration of crizotinib for 7 days, there was an increase in the levels of ALT and AST, indicating that the liver may have suffered some degree of damage. This is consistent with previous reports ( Harada et al, 2021 ; Tsukita et al, 2015 ).…”

Section: Discussionsupporting

confidence: 94%

Crizotinib inhibits the metabolism of tramadol by non-competitive suppressing the activities of CYP2D1 and CYP3A2

Gao,

Xu,

et al. 2024

PeerJ

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Objectives To investigate the interaction between tramadol and representative tyrosine kinase inhibitors, and to study the inhibition mode of drug-interaction. Methods Liver microsomal catalyzing assay was developed. Sprague-Dawley rats were administrated tramadol with or without selected tyrosine kinase inhibitors. Samples were prepared and ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) was used for analysis. Besides, liver, kidney, and small intestine were collected and morphology was examined by hematoxyline-eosin (H&E) staining. Meanwhile, liver microsomes were prepared and carbon monoxide differential ultraviolet radiation (UV) spectrophotometric quantification was performed. Results Among the screened inhibitors, crizotinib takes the highest potency in suppressing the metabolism of tramadol in rat/human liver microsome, following non-competitive inhibitory mechanism. In vivo, when crizotinib was co-administered, the AUC value of tramadol increased compared with the control group. Besides, no obvious pathological changes were observed, including cell morphology, size, arrangement, nuclear morphology with the levels of alanine transaminase (ALT) and aspartate transaminase (AST) increased after multiple administration of crizotinib. Meanwhile, the activities of CYP2D1 and CYP3A2 as well as the total cytochrome P450 abundance were found to be decreased in rat liver of combinational group. Conclusions Crizotinib can inhibit the metabolism of tramadol. Therefore, this recipe should be vigilant to prevent adverse reactions.

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Section: Discussionsupporting

confidence: 94%

Crizotinib inhibits the metabolism of tramadol by non-competitive suppressing the activities of CYP2D1 and CYP3A2

Gao,

Xu,

et al. 2024

PeerJ

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“…Indeed, a result of phase II trial showed limited efficacy of crizotinib to patients with ALK‐positive NSCLC treated with alectinib immediately before crizotinib monotherapy. 54 In our study, cMET activation was observed in JFCR‐059‐2 and was found to induce EGFR and HER3 tyrosine phosphorylation, as previously reported in MET amplification–mediated EGFR‐TKI gefitinib resistance. 55 However, in JFCR‐059‐2 cells, combination of alectinib or lorlatinib with crizotinib (as a cMET inhibitor) could induce almost complete eradication of tumor in an in vivo model.…”

Section: Discussionsupporting

confidence: 86%

“…Interestingly, these reports suggest that crizotinib cannot completely overcome this resistance despite its ability to inhibit cMET activation. Indeed, a result of phase II trial showed limited efficacy of crizotinib to patients with ALK‐positive NSCLC treated with alectinib immediately before crizotinib monotherapy 54 . In our study, cMET activation was observed in JFCR‐059‐2 and was found to induce EGFR and HER3 tyrosine phosphorylation, as previously reported in MET amplification–mediated EGFR‐TKI gefitinib resistance 55 .…”

Section: Discussionsupporting

confidence: 82%

Fibroblast growth factor receptor 3 overexpression mediates ALK inhibitor resistance in ALK‐rearranged non–small cell lung cancer

Sakashita

Yanagitani

Koike³

et al. 2022

Cancer Science

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The rearrangement of anaplastic lymphoma kinase (ALK) occurs in 3%‐5% of patients with non–small cell lung cancer (NSCLC) and confers sensitivity to ALK–tyrosine kinase inhibitors (TKIs). For the treatment of patients with ALK‐rearranged NSCLC, various additional ALK‐TKIs have been developed. Ceritinib is a second‐generation ALK‐TKI and has shown great efficacy in the treatment of patients with both newly diagnosed and crizotinib (a first‐generation ALK‐TKI)‐refractory ALK‐rearranged NSCLC. However, tumors can also develop ceritinib resistance. This may result from secondary ALK mutations, but other mechanisms responsible for this have not been fully elucidated. In this study, we explored the mechanisms of ceritinib resistance by establishing ceritinib‐resistant, echinoderm microtubule‐associated protein‐like 4 (EML4)‐ALK–positive H3122 cells and ceritinib‐resistant patient‐derived cells. We identified a mechanism of ceritinib resistance induced by bypass signals that is mediated by the overexpression and activation of fibroblast growth factor receptor 3 (FGFR3). FGFR3 knockdown by small hairpin RNA or treatment with FGFR inhibitors was found to resensitize the resistant cells to ceritinib in vitro and in vivo. FGFR ligands from either human serum or fetal bovine serum were able to activate FGFR3 and induce ceritinib resistance. A detailed analysis of ceritinib‐resistant patient‐derived specimens confirmed that tyrosine‐protein kinase Met (cMET) amplification induces ceritinib resistance. Amplified cMET counteractivated EGFR and/or Her3 and induced ceritinib resistance. These results reveal multiple ceritinib resistance mechanisms and suggest that ceritinib resistance might be overcome by identifying precise resistance mechanisms.

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Section: Discussionmentioning

confidence: 99%

“…MET gene amplification has previously been described as a bypass resistance mechanism to TKIs, first discovered in EGFR mutant NSCLC resistant to gefitinib 47 and subsequently observed in ALK rearranged and RET rearranged NSCLC. 26 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 More recently, MET gene amplification has been observed in ROS1+ lung cancers that progressed on lorlatinib, a next‐generation ROS1 TKI utilized to target some ROS1 mutations driven by first‐generation ROS1 TKIs. 22 To our knowledge, this represents the first case of MET‐mediated resistance to entrectinib in ROS1+ NSCLC, and importantly shows a novel mechanism involving ecDNA MET gene amplification.…”

Section: Discussionmentioning

confidence: 99%

MET gene amplification is a mechanism of resistance to entrectinib in ROS1+ NSCLC

Tyler

Chen

et al. 2022

Thoracic Cancer

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Background: ROS1 tyrosine kinase inhibitors (TKIs) have demonstrated significant clinical benefit for ROS1+ NSCLC patients. However, TKI resistance inevitably develops through ROS1 kinase domain (KD) modification or another kinase driving bypass signaling. While multiple TKIs have been designed to target ROS1 KD mutations, less is known about bypass signaling in TKI-resistant ROS1+ lung cancers. Methods: Utilizing a primary, patient-derived TPM3-ROS1 cell line (CUTO28), we derived an entrectinib-resistant line (CUTO28-ER). We evaluated proliferation and signaling responses to TKIs, and utilized RNA sequencing, whole exome sequencing, and fluorescence in situ hybridization to detect transcriptional, mutational, and copy number alterations, respectively. We substantiated in vitro findings using a CD74-ROS1 NSCLC patient's tumor samples. Last, we analyzed circulating tumor DNA (ctDNA) from ROS1+ NSCLC patients in the STARTRK-2 entrectinib trial to determine the prevalence of MET amplification. Results: CUTO28-ER cells did not exhibit ROS1 KD mutations. MET TKIs inhibited proliferation and downstream signaling and MET transcription was elevated in CUTO28-ER cells. CUTO28-ER cells displayed extrachromosomal (ecDNA) MET amplification without MET activating mutations, exon 14 skipping, or fusions. The CD74-ROS1 patient samples illustrated MET amplification while receiving ROS1 TKI. Finally, two of 105 (1.9%) entrectinib-resistant ROS1+ NSCLC STARTRK-2 patients with ctDNA analysis at enrollment and disease progression displayed MET amplification. Conclusions: Treatment with ROS1-selective inhibitors may lead to MET-mediated resistance. The discovery of ecDNA MET amplification is noteworthy, as ecDNA is associated with more aggressive cancers. Following progression on ROS1-selective inhibitors, MET gene testing and treatments targeting MET should be explored to overcome MET-driven resistance.

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Crizotinib for recurring non‐small‐cell lung cancer with EML4‐ALK fusion genes previously treated with alectinib: A phase II trial

Cited by 8 publications

References 30 publications

Crizotinib inhibits the metabolism of tramadol by non-competitive suppressing the activities of CYP2D1 and CYP3A2

Crizotinib inhibits the metabolism of tramadol by non-competitive suppressing the activities of CYP2D1 and CYP3A2

Fibroblast growth factor receptor 3 overexpression mediates ALK inhibitor resistance in ALK‐rearranged non–small cell lung cancer

MET gene amplification is a mechanism of resistance to entrectinib in ROS1+ NSCLC

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