Article
Multidisciplinary Sciences
Samuel J. Rodgers, Lisa M. Ooms, Viola M. J. Oorschot, Ralf B. Schittenhelm, Elizabeth Nguyen, Sabryn A. Hamila, Natalie Rynkiewicz, Rajendra Gurung, Matthew J. Eramo, Absorn Sriratana, Clare G. Fedele, Franco Caramia, Sherene Loi, Genevieve Kerr, Helen E. Abud, Georg Ramm, Antonella Papa, Andrew M. Ellisdon, Roger J. Daly, Catriona A. McLean, Christina A. Mitchell
Summary: INPP4B functions as a tumor suppressor in triple negative breast cancer by converting PI(3,4)P-2 to PI(3)P. However, in PIK3CA-mutant ER+ breast cancers, INPP4B enhances cell proliferation and tumor growth by promoting PI3K alpha-dependent late endosome formation and trafficking that activates Wnt/beta -catenin signaling.
NATURE COMMUNICATIONS
(2021)
Article
Oncology
Yanyan Cai, Guotai Xu, Fan Wu, Flavia Michelini, Carmen Chan, Xuan Qu, Pier Selenica, Erik Ladewig, Pau Castel, Yuanming Cheng, Alison Zhao, Komal Jhaveri, Eneda Toska, Marta Jimenez, Alexandra Jacquet Jacquet, Alicia Tran-Dien, Fabrice Andre, Sarat Chandarlapaty, Jorge S. Reis-Filho, Pedram Razavi, Maurizio Scaltriti
Summary: This study identified genetic lesions of multiple negative regulators of mTORC1 that may limit the efficacy of PI3Ka inhibitors in breast cancer, proposing therapeutic strategies to prevent or revert this resistance. These findings may guide patient selection strategies for future clinical trials.
Article
Multidisciplinary Sciences
Xiao-Li Wei, Fu-Rong Liu, Ji-Hong Liu, Hong-Yun Zhao, Yang Zhang, Zhi-Qiang Wang, Miao-Zhen Qiu, Fei Xu, Qiu-Qiong Yu, Yi-Wu Du, Yan-Xia Shi, De-Sheng Wang, Feng-Hua Wang, Rui-Hua Xu
Summary: CYH33 demonstrates manageable safety profile and preliminary anti-tumor efficacy in solid tumors harboring PIK3CA mutations.
NATURE COMMUNICATIONS
(2022)
Article
Oncology
Min Zhu, Chao Wu, Xuan Wu, Ge Song, Mingyang Li, Qiong Wang
Summary: Our study found that the RNase subunit POP1 is upregulated in breast cancer cell lines and tissues, and higher POP1 expression is associated with poor outcomes. Overexpression of POP1 promotes cell progression in breast cancer cells, while silencing of POP1 induces cell cycle arrest. Mechanistically, POP1 interacts and activates the telomerase complex by stabilizing the telomerase RNA component (TERC), thus protecting telomeres from shortening during division. Overall, our findings suggest that POP1 may serve as a novel prognostic marker and therapeutic target for breast cancer management.
Article
Oncology
S. Dent, J. Cortes, Y-H Im, V Dieras, N. Harbeck, I. E. Krop, T. R. Wilson, N. Cui, F. Schimmoller, J. Y. Hsu, J. He, M. De Laurentiis, S. Sousa, P. Drullinsky, W. Jacot
Summary: The SANDPIPER study demonstrated that Taselisib plus fulvestrant significantly improved progression-free survival in patients with PIK3CA-mutant breast cancer. However, due to safety concerns and modest clinical benefit, the combination therapy does not have clinical utility.
ANNALS OF ONCOLOGY
(2021)
Article
Chemistry, Medicinal
Emily J. Hanan, Marie-Gabrielle Braun, Robert A. Heald, Calum MacLeod, Connie Chan, Saundra Clausen, Kyle A. Edgar, Charles Eigenbrot, Richard Elliott, Nicholas Endres, Lori S. Friedman, Emily Gogol, Xiao-Hui Gu, Rebecca Hong Thibodeau, Philip S. Jackson, James R. Kiefer, Jamie D. Knight, Michelle Nannini, Raman Narukulla, Amanda Pace, Jodie Pang, Hans E. Purkey, Laurent Salphati, Deepak Sampath, Stephen Schmidt, Steve Sideris, Kyung Song, Swathi Sujatha-Bhaskar, Mark Ultsch, Heidi Wallweber, Jianfeng Xin, SiewKuen Yeap, Amy Young, Yu Zhong, Steven T. Staben
Summary: This study optimized a series of benzoxazepin-oxazolidinone ATP-competitive inhibitors of PI3K alpha that also induce selective degradation of the mutant p110 alpha protein. Structure-based design led to potent inhibitors with over 300-fold selectivity and further optimization of pharmacokinetic properties resulted in excellent in vivo efficacy. Clinical candidate GDC-0077 (inavolisib) is now being evaluated in a Phase III clinical trial for treating patients with PIK3CA-mutant breast cancer.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Qiyun Shi, Juncheng Xuhong, Hao Tian, Man Qu, Yi Zhang, Jun Jiang, Xiaowei Qi
Summary: This systematic review and meta-analysis study examines the predictive and prognostic value of PIK3CA mutations in HER2-positive breast cancer treated with TKIs. The analysis of 17 studies involving 1706 patients shows that wild-type PIK3CA patients had higher complete response rates and objective response rates compared to mutated PIK3CA patients. Additionally, PIK3CA mutations were marginally associated with poorer progression-free survival and overall survival in metastatic breast cancer patients. Therefore, PIK3CA mutations can predict treatment response in HER2-positive breast cancer patients treated with TKI-containing regimens.
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
(2023)
Article
Biochemistry & Molecular Biology
Alexandra M. Simond, Tung Bui, Dongmei Zuo, Virginie Sanguin-Gendreau, Trisha Rao, Wayne A. Phillips, Robert D. Cardiff, William J. Muller
Summary: This study found that the p110 alpha(HR) mutation attenuates metastatic behavior and is associated with the formation of ductal carcinoma in situ (DCIS) in ErbB2-driven breast cancer.
Review
Oncology
Silvia Rita Vitale, Federica Martorana, Stefania Stella, Gianmarco Motta, Nicola Inzerilli, Michele Massimino, Elena Tirro, Livia Manzella, Paolo Vigneri
Summary: The PI3K pathway is commonly deregulated in breast cancer, leading to resistance to inhibitors. Mechanisms of resistance include PI3K alterations, pathway reactivation, and enhancement of survival pathways.
CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY
(2021)
Article
Oncology
Xiaoqing Cheng, Yirui Sun, Maureen Highkin, Nagalaxmi Vemalapally, Xiaohua Jin, Brandon Zhou, Julie L. Prior, Ashley R. Tipton, Shunqiang Li, Anton Iliuk, Samuel Achilefu, Ian S. Hagemann, John R. Edwards, Ron Bose
Summary: In HER2-mutated breast cancer, PIK3CA mutation activates p21-CDK4/6-cyclin D1 signaling to drive resistance to HER2-targeted therapies, which can be overcome using CDK4/6 inhibitors.
Article
Oncology
Kyung W. Song, Kyle A. Edgar, Emily J. Hanan, Marc Hafner, Jason Oeh, Mark Merchant, Deepak Sampath, Michelle A. Nannini, Rebecca Hong, Lilian Phu, William F. Forrest, Eric Stawiski, Stephen Schmidt, Nicholas Endres, Jane Guan, Jeffrey J. Wallin, Jonathan Cheong, Emile G. Plise, Gail D. Lewis Phillips, Laurent Salphati, Timothy P. Heffron, Alan G. Olivero, Shiva Malek, Steven T. Staben, Donald S. Kirkpatrick, Anwesha Dey, Lori S. Friedman
Summary: The PI3K inhibitors GDC-0077 and taselisib have a unique mechanism of action by degrading mutant p110a protein, leading to more potent inhibition of mutant PI3K pathway signaling and cell viability, and better maintenance of prolonged pathway suppression.
Article
Medicine, Research & Experimental
Sushmita Mustafi, Vladimir Camarena, Rehana Qureshi, David W. Sant, Zachary Wilkes, Daniel Bilbao, Joyce Slingerland, Susan B. Kesmodel, Gaofeng Wang
Summary: The study demonstrated that vitamin C can synergistically enhance the anti-cancer effects of buparlisib in treating PIK3CA-mutated triple negative breast cancer cells, leading to reduced dosage requirements and potential mitigation of dose-dependent side effects. Vitamin C modulates PI3K pathway gene expression, inhibits AKT phosphorylation, and works in coordination with buparlisib to inhibit cancer cell growth.
Review
Biochemistry & Molecular Biology
Farah Raheem, Suganya Arunachalam Karikalan, Felipe Batalini, Aya El Masry, Lida Mina
Summary: Endocrine therapy is the primary treatment for hormone receptor-positive breast cancer. However, advanced tumors often develop resistance to this therapy, which can be caused by alterations in the estrogen receptor pathway or upstream growth factor signaling pathways. Despite progress in this field, resistance remains a major limitation and challenge.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Silvia Arcucci, Fernanda Ramos-Delgado, Coralie Cayron, Nicole Therville, Marie-Pierre Gratacap, Celine Basset, Benoit Thibault, Julie Guillermet-Guibert
Summary: PI3Ks are important lipid kinases that produce phosphoinositides, with three classes including PI3Kα and PI3Kβ in vertebrates. These isoforms share similar protein domains and lipid substrate specificity. In addition to redundancy, PI3Kα and PI3Kβ cooperate in integrating specific signals for organ development, physiology, and disease.
BIOCHEMICAL JOURNAL
(2021)
Article
Oncology
Zhen Shi, Julia Wulfkuhle, Malgorzata Nowicka, Rosa Gallagher, Cristina Saura, Paolo G. Nuciforo, Isabel Calvo, Jay Andersen, Jose Luis Passos-Coelho, Miguel J. Gil-Gil, Begona Bermejo, Debra A. Pratt, Eva M. Ciruelos, Patricia Villagrasa, Matthew J. Wongchenko, Emanuel F. Petricoin, Mafalda Oliveira, Steven J. Isakoff
Summary: This study demonstrates the association between high baseline pAKT levels, mutations in PI3K/AKT pathway components, and the enriched benefit of ipatasertib in TNBC.
CLINICAL CANCER RESEARCH
(2022)