Cancer Research and Treatment

Original Articles

Combination of Niraparib and Lapatinib for Ovarian Cancer Treatment: Feiyun Jiang, Xingyu Liu, Yalan Wei, Yeping Ding, Wen Cai, Shanshan Xu, Bin Tang; Received May 6, 2025 Accepted July 28, 2025 Published online July 29, 2025; DOI: https://doi.org/10.4143/crt.2025.553 [Epub ahead of print]

Abstract PDF PubReader ePub: Purpose
Ovarian cancer is characterized by high malignancy, frequent recurrence with drug resistance, and poor 5-year survival rates. Although poly(ADP-ribose) polymerase (PARP) inhibitors like niraparib show efficacy in homologous recombination repair-deficient ovarian cancer, resistance often develops. This study aimed to evaluate the synergistic therapeutic potential of combining the epidermal growth factor receptor (EGFR) inhibitor lapatinib and the PARP inhibitor niraparib to evaluate combinatorial effects and enhance antitumor effects in ovarian cancer.
Materials and Methods
Lapatinib (EGFR inhibitor) and niraparib (PARP inhibitor) were screened from the U.S. Food and Drug Administration/China Food and Drug Administration–approved drug library. In vitro assays assessed ovarian cancer cell proliferation, clonogenicity, metastatic ability, and apoptosis. Mechanistic studies analyzed phosphorylation levels of EGFR, AKT, and ERK via biochemical assays. In vivo experiments were conducted to validate the antitumor efficacy of the drug combination.
Results
The lapatinib-niraparib combination synergistically suppressed ovarian cancer cell proliferation, inhibited clonogenic formation and metastasis, and induced apoptosis. Mechanistically, the dual therapy reduced phosphorylation of EGFR, AKT, and ERK, indicating suppression of downstream signaling pathways. Both in vitro and in vivo experiments demonstrated significant inhibition of ovarian cancer growth with the combination treatment.
Conclusion
EGFR/human epidermal growth factor receptor 2–expressing ovarian cancer cells responded to lapatinib and that a synergistic effect was observed when combined with niraparib. These findings highlight its promising clinical potential for improving outcomes in ovarian cancer patients.

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General

Phase 1/2a Study of Rivoceranib, a Selective VEGFR-2 Angiogenesis Inhibitor, in Patients with Advanced Solid Tumors: Yoon-Koo Kang, Min-Hee Ryu, Yong Sang Hong, Chang-Min Choi, Tae Won Kim, Baek-Yeol Ryoo, Jeong Eun Kim, John R. Weis, Rachel Kingsford, Cheol Hee Park, Seong Jang, Arlo McGinn, Theresa L. Werner, Sunil Sharma; Cancer Res Treat. 2024;56(3):743-750. Published online January 18, 2024; DOI: https://doi.org/10.4143/crt.2023.980

Abstract PDF Supplementary Material PubReader ePub

Purpose
This study aimed to report the results from an early-phase study of rivoceranib, an oral tyrosine kinase inhibitor highly selective for vascular endothelial growth factor receptor 2, in patients with advanced solid tumors.
Materials and Methods
In this open-label, single-arm, dose-escalating, multicenter three-part phase 1/2a trial, patients had advanced solid tumors refractory to conventional therapy. Part 1 evaluated the safety and pharmacokinetics of five ascending once-daily doses of rivoceranib from 81 mg to 685 mg. Part 2 evaluated the safety and antitumor activity of once-daily rivoceranib 685 mg. Part 3 was conducted later, due to lack of maximum tolerated dose determination in part 1, to evaluate the safety and preliminary efficacy of once-daily rivoceranib 805 mg in patients with unresectable or advanced gastric cancer.
Results
A total of 61 patients were enrolled in parts 1 (n=25), 2 (n=30), and 3 (n=6). In parts 1 and 2, patients were white (45.5%) or Asian (54.5%), and 65.6% were male. The most common grade ≥ 3 adverse events were hypertension (32.7%), hyponatremia (10.9%), and hypophosphatemia (10.9%). The objective response rate (ORR) was 15.2%. In part 3, dose-limiting toxicities occurred in two out of six patients: grade 3 febrile neutropenia decreased appetite, and fatigue. The ORR was 33%.
Conclusion
The recommended phase 2 dose of rivoceranib was determined to be 685 mg once daily, which showed adequate efficacy with a manageable safety profile (NCT01497704 and NCT02711969).

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Advances in Targeted and Systemic Therapy for Salivary Gland Carcinomas: Current Options and Future Directions
Sushanth Sreenivasan, Rahim Jiwani, Richard White, Veli Bakalov, Ryan Moll, Joseph Liput, Larisa Greenberg
Current Oncology.2025; 32(4): 232. CrossRef
Proteomics profiling reveals the potential targets of Apatinib inhibiting the proliferation of glioma U251 cell
Yuyu Zhang, Yunshan Li, Fang Xu, Liangyu Pan, Saihang Zhang, Panpan Zhang, Xia Qin, Zuxiao Yang, Wei Yang, Wei Zhang, Dezhi Kong
Biochemical and Biophysical Research Communications.2025; 775: 152148. CrossRef

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Breast cancer

Real-World Data of Pyrotinib-Based Therapy in Metastatic HER2-Positive Breast Cancer: Promising Efficacy in Lapatinib-Treated Patients and in Brain Metastasis: Ying Lin, Mingxi Lin, Jian Zhang, Biyun Wang, Zhonghua Tao, Yiqun Du, Sheng Zhang, Jun Cao, Leiping Wang, Xichun Hu; Cancer Res Treat. 2020;52(4):1059-1066. Published online April 24, 2020; DOI: https://doi.org/10.4143/crt.2019.633

Abstract PDF Supplementary Material PubReader ePub

Purpose
Pyrotinib is a newly-developed irreversible pan-ErbB receptor tyrosine kinase inhibitor. This study reported the first real-world data of pyrotinib-based therapy in metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), focusing on efficacy in lapatinib-treated patients and in brain metastasis.
Materials and Methods
One hundred thirteen patients with metastatic HER2-positive BC treated with pyrotinib-based therapy in Fudan University Shanghai Cancer Center under non-clinical trial settings from September 1, 2018 to March 1, 2019 were included.
Results
Over half patients have received more than two lines of systematic therapy and exposed to two or more kinds of anti-HER2 agents. Most patients received a combined therapy, commonly of pyrotinib plus capecitabine, or vinorelbine or trastuzumab. Median progression-free survival (PFS) was 6.3 months (range, 5.54 to 7.06 months) and objective response rate (ORR) was 29.5%, with two patients (1.9%) achieving complete response. Lapatinib-naïve patients had significantly longer PFS than lapatinib-treated patients (9.0 months vs. 5.4 months, p=0.001). ORR for lapatinib-treated patients was 23.2%. Thirty-one of 113 patients have brain metastasis. Median PFS was 6.7 months and intracranial ORR was 28%. For patients without concurrent radiotherapy and/or brain surgery, the ORR was very low (6.3%). But for patients receiving concurrent radiotherapy and/or brain surgery, the ORR was 66.7%, and three patients achieved complete response. Most common adverse event was diarrhea.
Conclusion
Pyrotinib-based therapy demonstrated promising effects in metastatic HER2-positive BC and showed activity in lapatinib-treated patients. For patients with brain metastasis, pyrotinib-based regimen without radiotherapy showed limited efficacy, but when combined with radiotherapy it showed promising intracranial control.

Citations

Citations to this article as recorded by

Comparison of the prognostic effect of pyrotinib plus trastuzumab and chemotherapy different lines therapy in HER2-positive advanced breast cancer
Yangqingqing Zhou, Hui Wang, Jiao Yang, Fan Wang, Danfeng Dong, Xiaoai Zhao, Le Wang, Ruiyuan He, Zhiping Ruan, Jin Yang
Journal of Chemotherapy.2025; 37(2): 135. CrossRef
Pyrotinib-assisted whole brain radiotherapy alleviates HER2-positive advanced breast cancer and brain metastases: a prospective study in patients
Fulin Zhou, Cui Zhang, Mingyuan He, Yu Ren, Hongshuang Yue, Zhihua Tan, Shaolin Zhang, Yong Li, Shu Liu
Frontiers in Neurology.2025;[Epub] CrossRef
Efficacy and safety of inetetamab-containing regimens in patients with HER2-positive metastatic breast cancer in first-line/second-line setting
Jian Zhang, Yuxin Mu, Hui Zhang, Chao Deng, Jiao Yang, Lu Gan, Qingmo Yang, Xuefeng Xu, Wanping Liang, Xiaowei Qi, Liang Xu
Frontiers in Oncology.2025;[Epub] CrossRef
Neurotoxicity-sparing radiotherapy for brain metastases in breast cancer: a narrative review
Dagmara Buczek, Renata Zaucha, Jacek Jassem
Frontiers in Oncology.2024;[Epub] CrossRef
HER2-positive metastatic breast cancer with brain metastases responds favorably to pyrotinib and trastuzumab-based treatment: A case report and literature review
Min-long Chen, Wenjie Yu, Binbin Cui, Yijian Yu, Zhaosheng Ma
Frontiers in Oncology.2023;[Epub] CrossRef
Efficacy and safety of inetetamab-containing regimens in patients with HER2-positive metastatic breast cancer: a real-world retrospective study in China
Xiaoyu Liu, Peng Zhang, Chao Li, Xiang Song, Zhaoyun Liu, Wenna Shao, Sumei Li, Xinzhao Wang, Zhiyong Yu
Frontiers in Oncology.2023;[Epub] CrossRef
Evolving management of HER2+ breast cancer brain metastases and leptomeningeal disease
Matthew N. Mills, Whitney King, Aixa Soyano, Yolanda Pina, Brian J. Czerniecki, Peter A. Forsyth, Hatem Soliman, Hyo S. Han, Kamran A. Ahmed
Journal of Neuro-Oncology.2022; 157(2): 249. CrossRef
Temporal Heterogeneity of HER2 Expression and Spatial Heterogeneity of 18F-FDG Uptake Predicts Treatment Outcome of Pyrotinib in Patients with HER2-Positive Metastatic Breast Cancer
Chengcheng Gong, Cheng Liu, Zhonghua Tao, Jian Zhang, Leiping Wang, Jun Cao, Yannan Zhao, Yizhao Xie, Xichun Hu, Zhongyi Yang, Biyun Wang
Cancers.2022; 14(16): 3973. CrossRef
Cost-Effectiveness of Pyrotinib Plus Capecitabine versus Lapatinib Plus Capecitabine for the Treatment of HER2-Positive Metastatic Breast Cancer in China: A Scenario Analysis of Health Insurance Coverage
Yuwen Bao, Zhuolin Zhang, Xuan He, Lele Cai, Xiao Wang, Xin Li
Current Oncology.2022; 29(9): 6053. CrossRef
An Insight into Molecular Targets of Breast Cancer Brain Metastasis
Mohammed Kaleem, Mahmood Hassan Dalhat, Lubna Azmi, Turky Omar Asar, Wasim Ahmad, Maimonah Alghanmi, Amal Almostadi, Torki A. Zughaibi, Shams Tabrez
International Journal of Molecular Sciences.2022; 23(19): 11687. CrossRef
Real-World Outcome and Prognostic Factors Among HER2-Positive Metastatic Breast Cancer Patients Receiving Pyrotinib-Based Therapy: A Multicenter Retrospective Analysis
Jing Liu, Xianglu Sun, Qianyu Du, Jinghao Yao, Mengfen Dai, Qianqian Cheng, Han Xu, Yawei Li, Xiuli Liu, Mingliang Zhang, Yongchun Zhou, Yan Yang
Breast Cancer: Targets and Therapy.2022; Volume 14: 491. CrossRef
Eribulin Efficacy on Brain Metastases in Heavily Pretreated Patients with Metastatic Breast Cancer
Renaud Sabatier, Johan Martin, Cécile Vicier, Mathilde Guérin, Audrey Monneur, Magali Provansal, Louis Tassy, Carole Tarpin, Jean-Marc Extra, Frédéric Viret, Anthony Goncalves
Journal of Clinical Medicine.2021; 10(6): 1272. CrossRef
Pyrotinib Combined With Vinorelbine in HER2-Positive Metastatic Breast Cancer: A Multicenter Retrospective Study
Yi Li, Yixuan Qiu, Huihui Li, Ting Luo, Wei Li, Hong Wang, Bin Shao, Biyun Wang, Rui Ge
Frontiers in Oncology.2021;[Epub] CrossRef
Multiple Administrations of Itraconazole Increase Plasma Exposure to Pyrotinib in Chinese Healthy Adults
Yueyue Liu, Qian Zhang, Chao Lu, Wei Hu
Drug Design, Development and Therapy.2021; Volume 15: 2485. CrossRef
Brain Metastases in HER2-Positive Breast Cancer: Current and Novel Treatment Strategies
Alejandro Garcia-Alvarez, Andri Papakonstantinou, Mafalda Oliveira
Cancers.2021; 13(12): 2927. CrossRef
Pyrotinib Plus Vinorelbine Versus Lapatinib Plus Capecitabine in Patients With Previously Treated HER2-Positive Metastatic Breast Cancer: A Multicenter, Retrospective Study
Yizhao Xie, Yi Li, Luo Ting, Die Sang, Peng Yuan, Wei Li, Huihui Li, Rui Ge, Biyun Wang
Frontiers in Oncology.2021;[Epub] CrossRef
The Efficacy of Pyrotinib as a Third- or Higher-Line Treatment in HER2-Positive Metastatic Breast Cancer Patients Exposed to Lapatinib Compared to Lapatinib-Naive Patients: A Real-World Study
D. J Ouyang, Q. T Chen, M. Anwar, N. Xie, Q. C. Ouyang, P. Z. Fan, L. Y. Qian, G. N. Chen, E. X. Zhou, L. Guo, X. W. Gu, B. N. Ding, X. H. Yang, L. P. Liu, C. Deng, Z. Xiao, J. Li, Y. Q. Wang, S. Zeng, Shouman Wang, Wenjun Yi
Frontiers in Pharmacology.2021;[Epub] CrossRef
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Akanksha Sharma, Lauren Singer, Priya Kumthekar
Cancers.2021; 14(1): 17. CrossRef

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Apatinib Combined with Local Irradiation Leads to Systemic Tumor Control via Reversal of Immunosuppressive Tumor Microenvironment in Lung Cancer: Li-jun Liang, Chen-xi Hu, Yi-xuan Wen, Xiao-wei Geng, Ting Chen, Guo-qing Gu, Lei Wang, You-you Xia, Yong Liu, Jia-yan Fei, Jie Dong, Feng-hua Zhao, Yiliyar Ahongjiang, Kai-yuan Hui, Xiao-dong Jiang; Cancer Res Treat. 2020;52(2):406-418. Published online September 3, 2019; DOI: https://doi.org/10.4143/crt.2019.296

Abstract PDF Supplementary Material PubReader ePub

Purpose
This study aimed to investigate the potential systemic antitumor effects of stereotactic ablative radiotherapy (SABR) and apatinib (a novel vascular endothelial growth factor receptor 2 inhibitor) via reversing the immunosuppressive tumor microenvironment for lung carcinoma.
Materials and Methods
Lewis lung cancer cells were injected into C57BL/6 mice in the left hindlimb (primary tumor; irradiated) and in the right flank (secondary tumor; nonirradiated). When both tumors grew to the touchable size, mice were randomly divided into eight treatment groups. These groups received normal saline or three distinct doses of apatinib (50 mg/kg, 150 mg/kg, and 200 mg/kg) daily for 7 days, in combination with a single dose of 15 Gy radiotherapy or not to the primary tumor. The further tumor growth/regression of mice were followed and observed.
Results
For the single 15 Gy modality, tumor growth delay could only be observed at the primary tumor. When combining SABR and apatinib 200 mg/kg, significant retardation of both primary and secondary tumor growth could be observed, indicated an abscopal effect was induced. Mechanism analysis suggested that programmed death-ligand 1 expression increased with SABR was counteract by additional apatinib therapy. Furthermore, when apatinib was combined with SABR, the composition of immune cells could be changed. More importantly, this two-pronged approach evoked tumor antigen–specific immune responses and the mice were resistant to another tumor rechallenge, finally, long-term survival was improved.
Conclusion
Our results suggested that the tumor microenvironment could be managed with apatinib, which was effective in eliciting an abscopal effect induced by SABR.

Citations

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Wenjuan Zhong, Shugui Wu, Rui Zhu, Huaqiu Shi, Wei Yu, Linfang Liu, Longqiu Wu
BMC Cancer.2026;[Epub] CrossRef
Antiangiogenic Treatment Facilitates the Abscopal Effect of Radiation Therapy Combined With Anti-PD-1 in Hepatocellular Carcinoma
Hailong Sheng, Yongyi Luo, Liting Zhong, Zhiyi Wang, Zhichao Sun, Xinna Gao, Xinrong He, Zhenru Zhu, Dehua Wu, Jingyuan Sun, Chuanhui Cao
International Journal of Radiation Oncology*Biology*Physics.2025; 121(2): 534. CrossRef
Interactions between radiotherapy resistance mechanisms and the tumor microenvironment
Dengxiong Li, Jie Wang, Xinrui Li, Zhipeng Wang, Qingxin Yu, Siang Boon Koh, Ruicheng Wu, Luxia Ye, Yiqing Guo, Uzoamaka Okoli, Alisha Pati-Alam, Eduardo Mota, Wuran Wei, Koo Han Yoo, William C. Cho, Dechao Feng, Susan Heavey
Critical Reviews in Oncology/Hematology.2025; 210: 104705. CrossRef
Combination of potassium oxonate with anti-PD-1 for the treatment of colorectal cancer
Yuanyuan Wang, Chenxi Hu, Tianpeng Du, Jiawen Li, Kaiyuan Hui, Xiaodong Jiang
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Cancer Medicine.2023; 12(4): 4434. CrossRef
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PeerJ.2021; 9: e12356. CrossRef

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BioPATH: A Biomarker Study in Asian Patients with HER2+ Advanced Breast Cancer Treated with Lapatinib and Other Anti-HER2 Therapy: Sung-Bae Kim, In-Gu Do, Janice Tsang, Tae-You Kim, Yoon-Sim Yap, Gerardo Cornelio, Gyungyub Gong, Soonmyung Paik, Suee Lee, Ting-Ying Ng, Sarah Park, Ho-Suk Oh, Joanne Chiu, Joohyuk Sohn, Moonhee Lee, Young-Jin Choi, Eun Mi Lee, Kyong-Hwa Park, Christos Nathaniel, Jungsil Ro; Cancer Res Treat. 2019;51(4):1527-1539. Published online June 4, 2019; DOI: https://doi.org/10.4143/crt.2018.598

Abstract PDF PubReader ePub

Purpose
BioPATH is a non-interventional study evaluating the relationship of molecular biomarkers (PTEN deletion/downregulation, PIK3CA mutation, truncated HER2 receptor [p95HER2], and tumor HER2 mRNA levels) to treatment responses in Asian patients with HER2+ advanced breast cancer treated with lapatinib and other HER2-targeted agents. Materials and Methods Female Asian HER2+ breast cancer patients (n=154) who were candidates for lapatinib-based treatment following metastasis and having an available primary tumor biopsy specimen were included. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, overall survival on lapatinib, correlation between biomarker status and PFS for any previous trastuzumab-based treatment, and conversion/conservation rates of the biomarker status between tissue samples collected at primary diagnosis and at recurrence/metastasis. Potential relationships between tumor mRNA levels of HER2 and response to lapatinib-based therapy were also explored.
Results
p95HER2, PTEN deletion/downregulation, and PIK3CA mutation did not demonstrate any significant co-occurrence pattern and were not predictive of clinical outcomes on either lapatinib-based treatment or any previous trastuzumab-based therapy in the metastatic setting. Proportions of tumors positive for p95HER2 expression, PIK3CA mutation, and PTEN deletion/down-regulation at primary diagnosis were 32%, 31.2%, and 56.2%, respectively. Despite limited availability of paired samples, biomarker status patterns were conserved in most samples. HER2 mRNA levels were not predictive of PFS on lapatinib.
Conclusion
The prevalence of p95HER2 expression, PIK3CA mutation, and PTEN deletion/downregulation at primary diagnosis were similar to previous reports. Importantly, no difference was observed in clinical outcome based on the status of these biomarkers, consistent with reports from other studies.

Citations

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PIK3CA Mutation is Associated with Poor Response to HER2-Targeted Therapy in Breast Cancer Patients
Ju Won Kim, Ah Reum Lim, Ji Young You, Jung Hyun Lee, Sung Eun Song, Nam Kwon Lee, Seung Pil Jung, Kyu Ran Cho, Cheol Yong Kim, Kyong Hwa Park
Cancer Research and Treatment.2023; 55(2): 531. CrossRef
Discordance of PIK3CA mutational status between primary and metastatic breast cancer: a systematic review and meta-analysis
Justus Rosin, Ella Svegrup, Antonios Valachis, Ioannis Zerdes
Breast Cancer Research and Treatment.2023; 201(2): 161. CrossRef
Association of PIK3CA mutation with outcomes in HER2-positive breast cancer treated with anti-HER2 therapy: A meta-analysis and bioinformatic analysis of TCGA‑BRCA data
Haizhu Chen, Xingbin Hu, Daquan Wang, Ying Wang, Yunfang Yu, Herui Yao
Translational Oncology.2023; 37: 101738. CrossRef
Comparison of PIK3CA Mutation Prevalence in Breast Cancer Across Predicted Ancestry Populations
Jessica W. Chen, Karthikeyan Murugesan, Justin Y. Newberg, Ethan S. Sokol, Heidi M. Savage, Thomas J. Stout, Sophia L. Maund, Katherine E. Hutchinson
JCO Precision Oncology.2022;[Epub] CrossRef
Breast Cancer: A Molecularly Heterogenous Disease Needing Subtype-Specific Treatments
Ugo Testa, Germana Castelli, Elvira Pelosi
Medical Sciences.2020; 8(1): 18. CrossRef

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FOXO1 Suppression is a Determinant of Acquired Lapatinib-Resistance in HER2-Positive Gastric Cancer Cells Through MET Upregulation: Jinju Park, Yiseul Choi, Young San Ko, Younghoon Kim, Jung-Soo Pyo, Bo Gun Jang, Min A Kim, Jae-Seon Lee, Mee Soo Chang, Jong-Wan Park, Byung Lan Lee; Cancer Res Treat. 2018;50(1):239-254. Published online March 24, 2017; DOI: https://doi.org/10.4143/crt.2016.580

Abstract PDF PubReader ePub

Purpose
Lapatinib is a candidate drug for treatment of trastuzumab-resistant, human epidermal growth factor receptor 2 (HER2)–positive gastric cancer (GC). Unfortunately, lapatinib resistance renders this drug ineffective. The present study investigated the implication of forkhead box O1 (FOXO1) signaling in the acquired lapatinib resistance in HER2-positive GC cells.
Materials and Methods
Lapatinib-resistant GC cell lines (SNU-216 LR2-8) were generated in vitro by chronic exposure of lapatinib-sensitive, HER2-positive SNU-216 cells to lapatinib. SNU-216 LR cells with FOXO1 overexpression were generated by stable transfection of a constitutively active FOXO1 mutant (FOXO1A3). HER2 and MET in SNU-216 LR cells were downregulated using RNA interference. The sensitivity of GC cells to lapatinib and/or cisplatin was determined by crystal violet assay. In addition, Western blot analysis, luciferase reporter assay and reverse transcription–polymerase chain reaction were performed.
Results
SNU-216 LR cells showed upregulations of HER2 and MET, but downregulation of FOXO1 compared to parental SNU-216 cells. FOXO1 overexpression in SNU-216 LR cells significantly suppressed resistance to lapatinib and/or cisplatin. In addition, FOXO1 negatively controlled HER2 and MET at the transcriptional level and was negatively controlled by these molecules at the post-transcriptional level. A positive crosstalk was shown between HER2 and MET, each of which increased resistance to lapatinib and/or cisplatin.
Conclusion
FOXO1 serves as an important linker between HER2 and MET signaling pathways through negative crosstalks and is a key regulator of the acquired lapatinib resistance in HER2-positive GC cells. These findings provide a rationale for establishing a novel treatment strategy to overcome lapatinib resistance in a subtype of GC patients.

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Saudi Journal of Biological Sciences.2021; 28(9): 5371. CrossRef
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