At a crossroads: how to translate the roles of PI3K in oncogenic and metabolic signalling into improvements in cancer therapy

Vasan, Neil; Cantley, Lewis C.

doi:10.1038/s41571-022-00633-1

Cited by 78 publications

(68 citation statements)

References 172 publications

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“…In melanoma, PTEN deletion or inactivating mutations are found in 12% of patients, and 3% of patients carried PIK3CA mutations [n = 471, TCGAmelanoma Firehose Legacy (cBioportal.org)]. However, activation of numerous tyrosine kinase receptors expressed on both melanoma and TNBC tumors leads to activation of both the PI3K/AKT/mTOR and MAPK pathways [10,11].…”

Section: Overview Of the Pi3k And Mapk Signaling Pathways And Their I...mentioning

confidence: 99%

Immunomodulatory Properties of PI3K/AKT/mTOR and MAPK/MEK/ERK Inhibition Augment Response to Immune Checkpoint Blockade in Melanoma and Triple-Negative Breast Cancer

Zhang

Richmond

Yan

2022

IJMS

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Hyperactivation of PI3K/AKT/mTOR and MAPK/MEK/ERK signaling pathways is commonly observed in many cancers, including triple-negative breast cancer (TNBC) and melanoma. Moreover, the compensatory upregulation of the MAPK/MEK/ERK pathway has been associated with therapeutic resistance to targeted inhibition of the PI3K/AKT/mTOR pathway, and vice versa. The immune-modulatory effects of both PI3K and MAPK inhibition suggest that inhibition of these pathways might enhance response to immune checkpoint inhibitors (ICIs). ICIs have become the standard-of-care for metastatic melanoma and are recently an option for TNBC when combined with chemotherapy, but alternative options are needed when resistance develops. In this review, we present the current mechanistic understandings, along with preclinical and clinical evidence, that outline the efficacy and safety profile of combinatorial or sequential treatments with PI3K inhibitors, MAPK inhibitors, and ICIs for treatment of malignant melanoma and metastatic TNBC. This approach may present a potential strategy to overcome resistance in patients who are a candidate for ICI therapy with tumors harboring either or both of these pathway-associated mutations.

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Section: Overview Of the Pi3k And Mapk Signaling Pathways And Their I...mentioning

confidence: 99%

Immunomodulatory Properties of PI3K/AKT/mTOR and MAPK/MEK/ERK Inhibition Augment Response to Immune Checkpoint Blockade in Melanoma and Triple-Negative Breast Cancer

Zhang

Richmond

Yan

2022

IJMS

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“…Thus, this principle could be confirmed in 2 studies. In fact, the PI3K/AKT signaling pathway is a central mechanism of signal transduction with an extraordinary significance for many physiological and pathophysiological processes 13 , 14 .…”

Section: New Data On the Therapy Of The Pi3k/akt/pten Signaling Pathwaymentioning

confidence: 99%

“…Somit konnte dieses Prinzip in 2 Studien bestätigt werden. In der Tat ist der PI3K/AKT-Signalweg ein zentraler Mechanismus der Signaltransduktion mit einem außerordentlichen Stellenwert für viele physiologische und pathophysiologische Prozesse 13 , 14 .…”

Section: Der Pik3ca -Pathway Als Zentraler Bes...unclassified

Update Breast Cancer 2022 Part 4 – Advanced-Stage Breast Cancer

Aktas

Fehm

Welslau

et al. 2022

Geburtshilfe Frauenheilkd

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For the treatment of patients with advanced HER2-negative hormone receptor-positive breast cancer, several substances have been introduced into practice in recent years. In addition, other drugs are under development. A number of studies have been published over the past year which have shown either an advantage for progression-free survival or for overall survival. This review summarizes the latest results, which have been published at current congresses or in specialist journals, and classifies them in the clinical treatment context. In particular, the importance of therapy with CDK4/6 inhibitors – trastuzumab deruxtecan, sacituzumab govitecan and capivasertib – is discussed. For trastuzumab deruxtecan, an overall survival benefit in HER2-negative breast cancer with low HER2 expression (HER2-low expression) was reported in the Destiny-Breast-04 study. Similarly, there was an overall survival benefit in the FAKTION study with capivasertib. The lack of overall survival benefit for palbociclib in the first line of therapy raises the question of clinical classification.

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“…Mechanistically, PI3Kα inhibition enhances ER signaling through loss of phosphorylation of the epigenetic regulator KMT2D by the PI3K effectors AKT and SGK ( 43 , 78 ), providing a rationale for epigenetic therapy in combination with PI3K inhibition in this setting. For recent reviews on PI3K inhibitors for cancer therapy see ( 79 – 81 ).…”

Section: Cross-talk Between Signaling Pathways and Hormone Receptorsmentioning

confidence: 99%

Epigenetic Mechanisms Influencing Therapeutic Response in Breast Cancer

Arruabarrena-Aristorena

Toska

2022

Front. Oncol.

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The majority of breast cancers are estrogen receptor (ER)+ and agents targeting the ER signaling pathway have markedly increased survival for women with breast cancer for decades. However, therapeutic resistance eventually emerges, especially in the metastatic setting. In the past decade disrupted epigenetic regulatory processes have emerged as major contributors to carcinogenesis in many cancer types. Aberrations in chromatin modifiers and transcription factors have also been recognized as mediators of breast cancer development and therapeutic outcome, and new epigenetic-based therapies in combination with targeted therapies have been proposed. Here we will discuss recent progress in our understanding of the chromatin-based mechanisms of breast tumorigenesis, how these mechanisms affect therapeutic response to standard of care treatment, and discuss new strategies towards therapeutic intervention to overcome resistance.

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At a crossroads: how to translate the roles of PI3K in oncogenic and metabolic signalling into improvements in cancer therapy

Cited by 78 publications

References 172 publications

Immunomodulatory Properties of PI3K/AKT/mTOR and MAPK/MEK/ERK Inhibition Augment Response to Immune Checkpoint Blockade in Melanoma and Triple-Negative Breast Cancer

Immunomodulatory Properties of PI3K/AKT/mTOR and MAPK/MEK/ERK Inhibition Augment Response to Immune Checkpoint Blockade in Melanoma and Triple-Negative Breast Cancer

Update Breast Cancer 2022 Part 4 – Advanced-Stage Breast Cancer

Epigenetic Mechanisms Influencing Therapeutic Response in Breast Cancer

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