Cancer Research and Treatment

Original Articles

Differential Efficacy of Alpelisib by PIK3CA Mutation Site in Head and Neck Squamous Cell Carcinoma: An Analysis from the KCSG HN 15-16 TRIUMPH Trial: Kyoo Hyun Kim, Shinwon Hwang, Min Kyoung Kim, Keon-Uk Park, Tak Yun, Keun-Wook Lee, Joo Hang Kim, Bhumsuk Keam, Byoung Chul Cho, So Yeon Oh, Sang Hee Cho, Sangwoo Kim, Sung-Bae Kim, Min Hee Hong, Hye Ryun Kim; Received December 11, 2024 Accepted January 27, 2025 Published online January 31, 2025; DOI: https://doi.org/10.4143/crt.2024.1195 [Accepted]

Purpose
The TRIUMPH trial was a biomarker-driven umbrella trial for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). This analysis focuses on the PIK3CAɑ inhibitor alpelisib (arm 1) in patients with phosphoinositide 3-kinase (PI3K) pathway alterations.
Materials and Methods
Patients with PI3K pathway altered tumors were enrolled in the alpelisib arm of the TRIUMPH study. We conducted a detailed analysis of the correlation between PI3K pathway mutations and treatment outcomes including disease control rate (DCR), overall survival (OS), and progression-free survival (PFS).
Results
From Oct 2017 and Aug 2020, 203 were enrolled, with 42 treated with alpelisib. Response evaluation was possible for 33 patients. Genomic profiles revealed PIK3CA amplifications in 26.2%, and point mutations in E542K (26.2%), E545K (23.8%), and H1047R (9.5%). Neither PIK3CA amplification nor co-occurring TP53 mutations had a notable influence on alpelisib response or survival outcomes. Although the overall response rates were similar between helical domain mutations (E542, E545) and kinase domain mutations (H1047), patients with H1047 mutations exhibited significantly poorer PFS compared to those with non-H1047 PIK3CA alterations (1.6 vs. 7.3 months, p=0.017). OS in patients with H1047 kinase domain mutations showed a trend toward being shorter compared to others, though this difference did not reach statistical significance.
Conclusion
Alpelisib showed differential efficacy based on PI3K pathway alterations in patients with R/M HNSCC and was well-tolerated. These findings suggest the usefulness of NGS testing-based decision-making when using the targeted agents in R/M HNSCC. We need to confirm results in larger cohorts.

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PIK3CA Mutations: Are They a Relevant Target in Adult Diffuse Gliomas?
Ana Tomás, Marta Pojo
International Journal of Molecular Sciences.2025; 26(11): 5276. CrossRef

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Lung and Thoracic cancer

MLL4 Regulates the Progression of Non–Small-Cell Lung Cancer by Regulating the PI3K/AKT/SOX2 Axis: Yang Yang, Rongfang Qiu, Qiaoyou Weng, Ziwei Xu, Jingjing Song, Siyu Zhao, Miaomiao Meng, Dengke Zhang, Chunli Kong, Hailin Wang, Min Xu, Zhongwei Zhao, Jiansong Ji; Cancer Res Treat. 2023;55(3):778-803. Published online January 26, 2023; DOI: https://doi.org/10.4143/crt.2022.1042

Abstract PDF Supplementary Material PubReader ePub

Purpose
Mixed-lineage leukemia protein 4 (MLL4/KMT2D) is a histone methyltransferase, and its mutation has been reported to be associated with a poor prognosis in many cancers, including lung cancer. We investigated the function of MLL4 in lung carcinogenesis.
Materials and Methods
RNA sequencing (RNA-seq) in A549 cells transfected with control siRNA or MLL4 siRNA was performed. Also, we used EdU incorporation assay, colony formation assays, growth curve analysis, transwell invasion assays, immunohistochemical staining, and in vivo bioluminescence assay to investigate the function of MLL4 in lung carcinogenesis.
Results
We found that MLL4 expression was downregulated in non–small cell lung cancer (NSCLC) tissues compared to adjacent normal tissues and tended to decrease with disease stage progression. We analyzed the transcriptomes in control and MLL4- deficient cells using high-throughput RNA deep sequencing (RNA-seq) and identified a cohort of target genes, such as SOX2, ATF1, FOXP4, PIK3IP1, SIRT4, TENT5B, and LFNG, some of which are related to proliferation and metastasis. Our results showed that low expression of MLL4 promotes NSCLC cell proliferation and metastasis and is required for the maintenance of NSCLC stem cell properties.
Conclusion
Our findings identify an important role of MLL4 in lung carcinogenesis through transcriptional regulation of PIK3IP1, affecting the PI3K/AKT/SOX2 axis, and suggest that MLL4 could be a potential prognostic indicator and target for NSCLC therapy.

Citations

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KMT2D Induces M1 Macrophage Polarization to Repress Non-small Cell Lung Cancer Progression via Transcription Activation of ITGAL
Wen-Tao Wang, Jie Yang, Peng-Fei Jiang
Iranian Journal of Pharmaceutical Research.2025;[Epub] CrossRef
A positive feedback loop of OTUD1 and c-Jun driven by leptin expedites stemness maintenance in ovarian cancer
Jingtao Wang, Fan Yang, Yurou Chen, Yuzhu Xing, Juyuan Huang, Jing Cao, Jiaqiang Xiong, Yanyan Liu, Qiuyan Zhao, Manwen Luo, Jie Xiong, Guanlan Fan, Qiongying Lyu, Feng Li, Wei Zhang
Oncogene.2025;[Epub] CrossRef
TENT5/FAM46: An Enigmatic Family of Secretory Tuners
Daniel Lacidogna, Sara Pennacchio, Enrico Milan
Traffic.2025;[Epub] CrossRef
Role and potential therapeutic value of histone methyltransferases in drug resistance mechanisms in lung cancer
Linxiang Zhang, Xueying Zhang, Yan Shi, Yuhan Ni, Jiaojiao Fei, Zhixin Jin, Wenjuan Li, Xiaojing Wang, Nan Wu
Frontiers in Oncology.2024;[Epub] CrossRef
The multifaceted role of SOX2 in breast and lung cancer dynamics
Kiavash Hushmandi, Seyed Hassan Saadat, Seyedalireza Mirilavasani, Salman Daneshi, Amir Reza Aref, Noushin Nabavi, Rasoul Raesi, Afshin Taheriazam, Mehrdad Hashemi
Pathology - Research and Practice.2024; 260: 155386. CrossRef
PIK3IP1: structure, aberration, function, and regulation in diseases
Yingjie Jia, Pengxing He, Xubin Ma, Kaili Lv, Ying Liu, Yichao Xu
European Journal of Pharmacology.2024; 977: 176753. CrossRef
UBQLN4 promotes the proliferation and invasion of non-small cell lung cancer cell by regulating PI3K/AKT pathway
Li He, Heng Chen, Bin Ruan, Li He, Ming Luo, Yulun Fu, Rui Zou
Journal of Cancer Research and Clinical Oncology.2024;[Epub] CrossRef
Role of histone methyltransferase KMT2D in BMSC osteogenesis via AKT signaling
Zhichun Zhang, Yanyan Guo, Xuejun Gao, Xiaoyan Wang, Chanyuan Jin
Regenerative Therapy.2024; 26: 775. CrossRef
Landscape of targeted therapies for lung squamous cell carcinoma
Qiuxuan Chen, Xiaoshuo Zheng, Weiting Cheng, Jian Li
Frontiers in Oncology.2024;[Epub] CrossRef

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Breast cancer

Elevated Expression of RIOK1 Is Correlated with Breast Cancer Hormone Receptor Status and Promotes Cancer Progression: Zhiqi Huang, Xingyu Li, Tian Xie, Changjiang Gu, Kan Ni, Qingqing Yin, Xiaolei Cao, Chunhui Zhang; Cancer Res Treat. 2020;52(4):1067-1083. Published online May 8, 2020; DOI: https://doi.org/10.4143/crt.2020.187

Abstract PDF Supplementary Material PubReader ePub

Purpose
RIOK1 has been proved to play an important role in cancer cell proliferation and migration in various types of cancers—such as colorectal and gastric cancers. However, the expression of RIOK1 in breast cancer (BC) and the relationship between RIOK1 expression and the development of BC are not well characterized. In this study, we assessed the expression of RIOK1 in BC and evaluated the mechanisms underlying its biological function in this disease context.
Materials and Methods
We used immunohistochemistry, western blot and quantitative real-time polymerase chain reaction to evaluate the expression of RIOK1 in BC patients. Then, knockdown or overexpression of RIOK1 were used to evaluate the effect on BC cells in vitro and in vivo. Finally, we predicted miR-204-5p could be a potential regulator of RIOK1.
Results
We found that the expression levels of RIOK1 were significantly higher in hormone receptor (HR)–negative BC patients and was associated with tumor grades (p=0.010) and p53 expression (p=0.008) and survival duration (p=0.011). Kaplan-Meier analysis suggested a tendency for the poor prognosis. In vitro, knockdown of RIOK1 could inhibit proliferation, invasion, and induced apoptosis in HR-negative BC cells and inhibited tumorigenesis in vivo, while overexpression of RIOK1 promoted HR-positive tumor progression. MiR-204-5p could regulate RIOK1 expression and be involved in BC progression.
Conclusion
These findings indicate that RIOK1 expression could be a biomarker of HR-negative BC, and it may serve as an effective prognostic indicator and promote BC progression.

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Establishment of a 5-gene risk model related to regulatory T cells for predicting gastric cancer prognosis
Gang Hu, Ningjie Sun, Jiansong Jiang, Xiansheng Chen
Cancer Cell International.2020;[Epub] CrossRef

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A Novel, Potent, Small Molecule AKT Inhibitor Exhibits Efficacy against Lung Cancer Cells In Vitro: Saketh S. Dinavahi, Rajagopalan Prasanna, Sriram Dharmarajan, Yogeeswari Perumal, Srikant Viswanadha; Cancer Res Treat. 2015;47(4):913-920. Published online January 2, 2015; DOI: https://doi.org/10.4143/crt.2014.057

Abstract PDF PubReader ePub

Purpose
Anomalies of Akt regulation, including overexpression in lung cancer, impart resistance to conventional chemotherapy and radiation, thereby implicating this kinase as a therapeutic intervention point. A novel scaffold of Akt inhibitors was developed through virtual screening of chemical databases available at Birla Institute of Technology and Science, Pilani, Hyderabad, based on docking studies using Maestro. A benzothienopyrimidine derivative (BIA-6) was identified as a potential lead molecule that inhibited Akt1 enzyme activity with an IC50 of 256 nM.
Materials and Methods
BIA-6 was tested for in vitro Akt1 inhibition using a fluorescence resonance energy transfer kit. Anti-proliferative activity was tested in NCI-H460, A549, NCI-H1975, and NCI-H2170 cell lines. The effect of the compound on p-Akt (S473) was estimated.
Results
BIA-6 allosterically caused a dose dependent reduction of growth of cell lines with a half maximal growth inhibition (GI50) range of 0.49 μM to 6.6 μM. Cell cycle analysis indicated that BIA-6 caused a G1 phase arrest at < 100 nM but led to apoptosis at higher doses. BIA- 6 also exhibited synergism with standard chemotherapeutic agents.
Conclusion
BIA-6 is a novel, allosteric Akt inhibitor with potent anti-cancer activity in lung cancer cell lines, that effectively blocks the phosphoinositide-3 kinase/Akt pathway with a high margin selectivity towards normal cells.

Citations

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Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development
Saketh S. Dinavahi, Yu-Chi Chen, Raghavendra Gowda, Pavan Kumar Dhanyamraju, Kishore Punnath, Dhimant Desai, Arthur Berg, Scot R. Kimball, Shantu Amin, Jin-Ming Yang, Gavin P. Robertson
International Journal of Molecular Sciences.2022; 23(7): 3481. CrossRef
Targeting WEE1/AKT Restores p53-Dependent Natural Killer–Cell Activation to Induce Immune Checkpoint Blockade Responses in “Cold” Melanoma
Saketh S. Dinavahi, Yu-Chi Chen, Kishore Punnath, Arthur Berg, Meenhard Herlyn, Momeneh Foroutan, Nicholas D. Huntington, Gavin P. Robertson
Cancer Immunology Research.2022; 10(6): 757. CrossRef
Development of a Novel Multi-Isoform ALDH Inhibitor Effective as an Antimelanoma Agent
Saketh S. Dinavahi, Raghavendra Gowda, Krishne Gowda, Christopher G. Bazewicz, Venkat R. Chirasani, Madhu Babu Battu, Arthur Berg, Nikolay V. Dokholyan, Shantu Amin, Gavin P. Robertson
Molecular Cancer Therapeutics.2020; 19(2): 447. CrossRef
Screening of Pleural Mesothelioma Cell Lines for Kinase Activity May Identify New Mechanisms of Therapy Resistance in Patients Receiving Platin-Based Chemotherapy
Sabrina Borchert, Pia-Maria Suckrau, Michael Wessolly, Elena Mairinger, Balazs Hegedus, Thomas Hager, Thomas Herold, Wildfried E. E. Eberhardt, Jeremias Wohlschlaeger, Clemens Aigner, Agnes Bankfalvi, Kurt Werner Schmid, Robert F. H. Walter, Fabian D. Mai
Journal of Oncology.2019; 2019: 1. CrossRef
Moving Synergistically Acting Drug Combinations to the Clinic by Comparing Sequential versus Simultaneous Drug Administrations
Saketh S. Dinavahi, Mohammad A. Noory, Raghavendra Gowda, Joseph J. Drabick, Arthur Berg, Rogerio I. Neves, Gavin P. Robertson
Molecular Pharmacology.2018; 93(3): 190. CrossRef
Novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivative, MHY-449, induces cell cycle arrest and apoptosis via the downregulation of Akt in human lung cancer cells
HYUN SOOK LIM, YONG JUNG KANG, BOKYUNG SUNG, SEON HEE KIM, MIN JEONG KIM, HYE RIM KIM, SEONG JIN KIM, YUNG HYUN CHOI, HYUNG RYONG MOON, HAE YOUNG CHUNG, NAM DEUK KIM
Oncology Reports.2015; 34(5): 2431. CrossRef

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