IRS2 Amplification as a Predictive Biomarker in Response to Ceritinib in Small Cell Lung Cancer

Lee, Mi-Sook; Jung, Kyungsoo; Song, Ji-Young; Sung, Moon Su; Ahn, Sangtae; Lee, Boram; Oh, Doo‐Yi; Choi, Yoon‐La

doi:10.1016/j.omto.2019.12.009

Cited by 6 publications

(3 citation statements)

References 28 publications

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“…In the xenograft model, treatment with ceritinib at a dosage of 50 mg/kg resulted in a significant reduction in tumor weight and volume across all the mice (Figure 6). This outcome aligns with a previous xenograft study utilizing the A375P melanoma cell line, which also lacked ALK rearrangements or mutations [62].…”

Section: Discussionsupporting

confidence: 89%

Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation

Myint,

Balasubramanian,

Venkatraman

et al. 2024

Pharmaceuticals

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Cholangiocarcinoma (CCA) is a difficult-to-treat cancer, with limited therapeutic options and surgery being the only curative treatment. Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients. Receptor tyrosine kinases (RTKs) are aberrantly expressed in CCAs encompassing potential therapeutic opportunity. Hence, 112 RTK inhibitors were screened in KKU-M213 cells, and ceritinib, an approved targeted therapy for ALK-fusion gene driven cancers, was the most potent candidate. Ceritinib’s cytotoxicity in CCA was assessed using MTT and clonogenic assays, along with immunofluorescence, western blot, and qRT-PCR techniques to analyze gene expression and signaling changes. Furthermore, the drug interaction relationship between ceritinib and cisplatin was determined using a ZIP synergy score. Additionally, spheroid and xenograft models were employed to investigate the efficacy of ceritinib in vivo. Our study revealed that ceritinib effectively killed CCA cells at clinically relevant plasma concentrations, irrespective of ALK expression or mutation status. Ceritinib modulated multiple signaling pathways leading to the inhibition of the PI3K/Akt/mTOR pathway and activated both apoptosis and autophagy. Additionally, ceritinib and cisplatin synergistically reduced CCA cell viability. Our data show ceritinib as an effective treatment of CCA, which could be potentially explored in the other cancer types without ALK mutations.

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Section: Discussionsupporting

confidence: 89%

Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation

Myint,

Balasubramanian,

Venkatraman

et al. 2024

Pharmaceuticals

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show abstract

“…Moreover, IRS2 is thought to be a candidate driver oncogene on 13q34 in colorectal cancer. Ampification of IRS2 was observed in 2-5% of SCLC patients [13,25], and ceritinib, a dual inhibitor of ALK/IGF-1R, could efficiently inhibit the growth of SCLC with IRS2 amplification in vitro and in vivo. Moreover, We found KARS mutation and IRS2 amplification co-occurrence in 3 patients.…”

Section: Discussionmentioning

confidence: 99%

The next generation sequencing of cancer-related genes in small cell neuroendocrine carcinoma of the cervix

Pei

Xiang

Chen

et al. 2021

Gynecologic Oncology

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“…However, it is difficult to make a direct comparison with the result of the previous study because various factors that can affect the result, such as the PET image features used, the applied target genes, tumor segmentation method, scanner, image protocol, and analyzing strategy are all different. In SQCC, four major genes were associated with 6 PET image features: ERCC2 25 , IRS2 26 , NOTCH1 27 , and XPO1 28 , which functions as a DNA repair gene 25 , mediates effects of insulin and other cytokines 26 , plays a role in cell growth, division, differentiation, and apoptosis 27 , and mediates the nuclear export of proteins and RNAs 28 , respectively. Image clusters were associated with the p53, WNT, and cell cycle pathways.…”

Section: Discussionmentioning

confidence: 99%

Metabolic radiogenomics in lung cancer: associations between FDG PET image features and oncogenic signaling pathway alterations

Kim¹,

Kim²,

Cha³

et al. 2020

Sci Rep

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this study investigated the associations between image features extracted from tumor 18 F-fluorodeoxyglucose (FDG) uptake and genetic alterations in patients with lung cancer. A total of 137 patients (age, 62.7 ± 10.2 years) who underwent FDG positron emission tomography/computed tomography (PET/CT) and targeted deep sequencing analysis for a tumor lesion, comprising 61 adenocarcinoma (ADC), 31 squamous cell carcinoma (SQCC), and 45 small cell lung cancer (SCLC) patients, were enrolled in this study. From the tumor lesions, 86 image features were extracted, and 381 genes were assessed. PET features were associated with genetic mutations: 41 genes with 24 features in ADC; 35 genes with 22 features in SQCC; and 43 genes with 25 features in SCLC (FDR < 0.05). Clusters based on PET features showed an association with alterations in oncogenic signaling pathways: Cell cycle and WNT signaling pathways in ADC (p = 0.023, p = 0.035, respectively); Cell cycle, p53, and WNT in SQCC (p = 0.045, 0.009, and 0.029, respectively); and TGFβ in SCLC (p = 0.030). In addition, SUV peak and SUV max were associated with a mutation of the TGFβ signaling pathway in ADC (FDR = 0.001, < 0.001). In this study, PET image features had significant associations with alterations in genes and oncogenic signaling pathways in patients with lung cancer. Radiogenomics, merging medical imaging data and genomic information, has great potential in the era of personalized medicine 1-4. Genomic information could enable physicians to select appropriate management strategies according to the genetic alterations in an individual patient with cancer 5. Nevertheless, the application of genomic medicine in the field of oncology has shortcomings because tumors have genetic and phenotypic diversities even within a single mass 5-7. Such intra-tumor heterogeneity eventually drives treatment failure and disease progression 7-9. To overcome it, multiple and sequential biopsies should be conducted to identify all the genetic alterations within the whole tumor throughout the course of disease progression within a patient, which is not always feasible in routine clinical practice. Therefore, the search for noninvasive techniques that reflect genetic alterations in multiple sites and at multiple time points is important because such techniques could improve patient care. Various features from medical images of a tumor could be surrogate markers that predict the alteration of particular genetic pathways. A known association between image features and genetic alterations has a potential as a useful additional information to improve decision making of biopsies, which could create new, accessible management strategies for patients with cancer 4,6,10 .

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IRS2 Amplification as a Predictive Biomarker in Response to Ceritinib in Small Cell Lung Cancer

Cited by 6 publications

References 28 publications

Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation

Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation

The next generation sequencing of cancer-related genes in small cell neuroendocrine carcinoma of the cervix

Metabolic radiogenomics in lung cancer: associations between FDG PET image features and oncogenic signaling pathway alterations

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