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Allosteric PI3K-alpha inhibition overcomes on-target resistance to orthosteric inhibitors mediated by secondary PIK3CA mutations.

Author: BardiaAditya, BarnesHaley, ChevalierNicholas, CorcoranRyan B, DanyshBrian P, EhnstromSara, EllisHaley, Fece de la CruzFerran, GetzGad, GunaydinHakan, IsakoffSteven J, JiYongli, JuricDejan, KehlmannAllison M, KimJanice S, LauKayao, LennerzJochen K, LeshchinerIgnaty, MartinElizabeth E, NordenBryanna L, PapatheodoridiAlkistis, ParidaLaxmi, PazolliErmira, PierceLevi, SanidasIoannis, SpringLaura M, StavridiAnastasia-Maria, VarkarisAndreas, WulfGerburg M, YuanXin

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Overview

PIK3CA mutations are common in breast cancer, and the PI3K-alpha (PI3Ka)-selective inhibitor alpelisib is FDA-approved for treating these tumors. However, acquired resistance to PI3Ka inhibitors is a significant challenge. This study identified various genomic alterations that contribute to resistance, including PTEN loss, activating AKT1 mutations, and secondary PIK3CA mutations. The findings highlight the need for novel PI3Ka inhibitors that can overcome these resistance mechanisms.
Paper Details　
Original Abstract of the Article :
PIK3CA mutations occur in ~8% of cancers, including ~40% of HR-positive breast cancers, where the PI3K-alpha (PI3Ka)-selective inhibitor alpelisib is FDA-approved in combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as PTEN loss, clinical acquired resis...See full text at original site
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引用元：
https://doi.org/10.1158/2159-8290.CD-23-0704

データ提供：米国国立医学図書館（NLM）

Overcoming On-Target Resistance to Orthosteric Inhibitors Mediated by Secondary PIK3CA Mutations

The fight against cancer can be seen as a battle in a vast and unforgiving desert. Cancer cells, like resilient desert plants, often develop resistance to medications. This study focuses on understanding how cancer cells develop resistance to PI3K-alpha inhibitors, which are medications used to treat certain types of cancer. Researchers utilized a combination of methods, including serial liquid biopsies and rapid autopsies, similar to carefully studying the soil and plants in the desert to understand how they adapt to changing conditions. The findings reveal that secondary mutations in the PIK3CA gene can lead to resistance to these inhibitors.

A New Weapon in the Fight Against Cancer

This study suggests that a new class of PI3K-alpha inhibitors, known as allosteric inhibitors, might be effective in overcoming resistance to existing PI3K-alpha inhibitors. These allosteric inhibitors work in a different way, similar to finding a new water source that bypasses the existing, depleted source. This discovery offers a potential new strategy for treating cancers that have developed resistance to traditional PI3K-alpha inhibitors.

Hope for Patients with PIK3CA-Mutated Cancers

This research offers hope for patients with PIK3CA-mutated cancers, who often face challenges in finding effective treatment options. It emphasizes the importance of ongoing research to develop new and innovative cancer therapies. The study also highlights the need for personalized medicine approaches to effectively target the specific genetic alterations driving cancer development.

Dr. Camel's Conclusion

This study provides a roadmap for navigating the complex terrain of cancer drug resistance. By uncovering the mechanisms behind resistance and developing novel inhibitors, researchers are forging a path towards more effective treatments for patients with PIK3CA-mutated cancers. This ongoing battle against cancer requires relentless innovation and a deep understanding of the intricate workings of both cancer cells and the human body.

Date :
  1. Date Completed n.d.
  2. Date Revised 2023-11-02
Further Info :

Pubmed ID

37916958

DOI: Digital Object Identifier

10.1158/2159-8290.CD-23-0704

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SNS
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in preparation
Languages

English

Positive IndicatorAn AI analysis index that serves as a benchmark for how positive the results of the study are. Note that it is a benchmark and requires careful interpretation and consideration of different perspectives.

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