Nat Commun Mao Ninghui/Zhang Zeda propose precise treatment strategies for different subtypes of prostate cancer with PI3K pathway mutations

Responsible editor | Enzyme's PI3K signaling pathway controls cell growth, division, absorption and utilization of nutrients, and is an important hub that connects signal transduction inside and outside the cell [1]
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While performing important cell biological functions, key gene mutations in the pathway are also one of the most common carcinogenic mutations in human tumors [2]
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In hormone-regulated tumors, such as breast cancer and prostate cancer, oncogenic driving variants are often manifested in the mutation/amplification/over-upregulation of the proto-oncogene PIK3CA/PIK3CB in the PI3K pathway, and the loss of the tumor suppressor gene PTEN
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For example, PIK3CA driver mutations occur in nearly 30% of breast cancers, while PTEN loss occurs in nearly 40% of advanced prostate cancers
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Because the activation variants of the PI3K signaling pathway are widespread in tumors, inhibiting the activity of the variant PI3K signaling pathway is considered to be a therapeutic method with great potential
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However, due to poor specificity and target toxicity, the early research of small molecule inhibitors for PI3K has not made breakthrough progress
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PI3K is a multi-subunit complex with catalytic function, and the most common type I holoenzyme complex function mainly depends on the catalytic subunit p110
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In the epidermal cell tissue, the activity of the two types of catalytic subunits, p110α (PIK3CA) and p110β (PIK3CB) play an important role in the catalytic activity of the PI3K complex
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In tumors with mutations in the PI3K signaling pathway, the catalytic activity of PI3K is often selectively dependent on different catalytic subunits
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For example, breast cancer with PIK3CA activating mutations mainly depends on p110α
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Based on this discovery, Novartis Pharma’s Phase III clinical trial SOLAR1 (NCT03056755), which ended in 2019, adopted a new p110α selective small molecule inhibitor BYL719 (Alpelisib), and was approved by the FDA for marketing in combination with fulvestrant.
Breast cancer patients with HR+/HER2-/PIK3CA mutations [3]
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While achieving success, there are also problems with the treatment plan based on targeting p110α.
Studies have found that in PTEN-deficient tumors, the activity of PI3K migrates from the p110α subunit to the p110β subunit, while selective inhibition of the p110β subunit It will cause the release of upstream negative feedback inhibition, thereby reactivating PI3K and reducing the therapeutic effect [4,5]
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There are no effective clinical interventions for tumors with PTEN deletion mutations
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On August 20, 2021, the Brett S.
Carver team of Memorial Sloan Kettering Cancer Research Center (co-authors Dr.
Mao Ninghui and Dr.
Zhang Zeda) published a translational medicine research result in Nature Communications, titled: Defining the therapeutic Selective dependencies for distinct subtypes of PI3K pathway-altered prostate cancers.
This study uses the tumor organoid platform for the first time to subdivide the molecular subtypes of prostate tumors with mutations in the PI3K signaling pathway.
The selection sensitivity of targeted therapy strategies provides the latest scientific basis for precise treatment of tumors with PI3K pathway mutations
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Prostate cancer is one of the most common tumors in men.
The loss of the negative regulator PTEN in the PI3K pathway accounts for 40% of advanced prostate cancer [6].
The traditional view is that PI3K drives this type of PTEN-deficient prostate tumor cells.
The signal mainly comes from p110β
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In this study, the authors used a patient-derived prostate tumor organoid (cancer organoid) platform as a preclinical pharmacological research model, and molecularly classified more than 20 tumor organoids according to the variation of the PI3K signaling pathway.
The selective small molecule inhibitor BYL719/AZD8186 of PI3K catalytic subunit p110α/p110β studied the sensitivity of prostate tumor organoids of different PI3K variant subtypes to two small molecule inhibitors
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The authors unexpectedly found that in PTEN-deficient prostate tumor organoids and cells, the driving signal of PI3K is not completely dependent on the p110β subunit, and some are more dependent on the p110α subunit
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CRISPR-Cas9 knockout of PTEN in p110α subunit-dependent tumor organoids also failed to change its dependence on p110α subunit
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Similarly, in the absence of PTEN, the exogenous expression of wild-type PTEN in p110β-dependent LNCaP cells does not change its inherent dependence on p110β
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Although PTEN-deficient prostate tumors still depend on the activity of p110α/p110β, previous studies have shown that due to the mutual negative feedback inhibition relationship between p110α and p110β, inhibiting any one of the catalytic subunits of p110 alone will cause another subunit.
Compensatory activation of the base, thereby weakening the overall inhibitory effect on the PI3K signaling pathway [4]
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Therefore, the dual-drug combination of p110α+p110β inhibitors can more effectively inhibit the PI3K activity in tumors
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At the same time, the authors also found that some tumor organoids have natural tolerance to the dual-drug combination of p110α+p110β inhibitors, and this tolerance depends on the loss of PTEN and the receptor tyrosine kinase on the cell surface.
IGF1R is highly expressed in the family
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Although genetic evidence indicates that IGF1R knockdown tumors have regained their response to p110α+p110β inhibitors, pharmacological data indicate that the triple-drug combination of IGF1R inhibitors and p110α+p110β inhibitors has strong toxicity.
It is not suitable for subsequent clinical development
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The author therefore adopted direct inhibition of AKT, the downstream signaling hub of PI3K, and found that the therapeutic effect was significant in the mouse model and no obvious side effects were observed
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Finally, the authors performed PI3K signaling pathway inhibition tests for PTEN wild-type, PTEN mutant deletion, p110α activating mutations, and p110β activating mutations in various prostate and breast cancers, looking for different molecular subtypes in tumors with PI3K mutations.
Whether it has similar or different sensitivity to the inhibition of this pathway
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Through cell lines, tumor organoids, and mouse models of patient tumor xenoplants, three main conclusions have been drawn: In general, PTEN wild-type tumors are more sensitive to direct inhibition of the upstream p110 catalytic subunit of PI3K, and among them Tumors with p110α activating mutations and p110β activating mutations are more effective against the corresponding small molecule inhibitors BYL719 (p110α-selective) or AZD8186 (p110β-selective), respectively
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Tumors with PTEN deletion mutants are more sensitive to direct inhibition of PI3K's downstream effector protein AKT (Ipatasertib).
In such tumor cells, the p110α/β mutation does not affect the sensitivity of the tumor to Ipatasertib
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When the receptor tyrosine kinases on the surface of tumor cells such as IGF1R are highly expressed, if the PTEN in the tumor cells is still in the wild state, the dual-drug combination of BYL719+AZD8186 will have a better effect
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If PTEN is missing in tumor cells, Ipatasertib will be more effective
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Figure 1: The response of different subtypes of PI3K pathway mutant prostate cancer and breast cancer cells to p110α/β or AKT inhibitors.
The combination of AKT inhibitor Ipatasertib and hormone therapy is currently undergoing phase III clinical trials (NCT03072238), and PTEN The missing state is a key biomarker for recruiting patients
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Due to the encouraging mid-term results reported recently, Ipatasertib is also expected to become the first small molecule inhibitor of the PI3K signaling pathway approved by the FDA in prostate tumors
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At the same time, about 70% of breast cancers carrying p110α mutations will develop PTEN deletion mutations after treatment with p110α inhibitors (BYL719), and the AKT inhibitor Ipatasertib will provide a new treatment option for these patients
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Figure 2: Precision treatment strategies for different subtypes of PI3K pathway mutant prostate cancer.
The co-first authors of this study are Dr.
Mao Ninghui and Dr.
Zhang Zeda from Memorial Sloan Kettering Cancer Research Center, and the corresponding authors are Memorial Sloan Kettering Professor Brett Carver, a urological oncologist at the Cancer Research Center
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Yu Chen, Neal Rosen, Charles Sawyer, Young Sun Lee of the Sloan Kettering Cancer Research Center and Andrew C.
Hsieh of the Fred Hutchinson Cancer Research Center also made important contributions to this research
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et al.
Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ.
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Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer.
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