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PI3K inhibitors: review and new strategies.

ABSTRACT: The search is on for effective specific inhibitors for PI3K? mutants. PI3K?, a critical lipid kinase, has two subunits, catalytic and inhibitory. PIK3CA, the gene that encodes the p110? catalytic subunit is a highly mutated protein in cancer. Dysregulation of PI3K? signalling is commonly associated with tumorigenesis and drug resistance. Despite its vast importance, only recently the FDA approved the first drug (alpelisib by Novartis) for breast cancer. A second (GDC0077), classified as PI3K? isoform-specific, is undergoing clinical trials. Not surprisingly, these ATP-competitive drugs commonly elicit severe concentration-dependent side effects. Here we briefly review PI3K? mutations, focus on PI3K drug repertoire and propose new, to-date unexplored PI3K? therapeutic strategies. These include (1) an allosteric and orthosteric inhibitor combination and (2) taking advantage of allosteric rescue mutations to guide drug discovery.

SUBMITTER: Zhang M

PROVIDER: S-EPMC7472334 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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PI3K inhibitors: review and new strategies.

Zhang Mingzhen M Jang Hyunbum H Nussinov Ruth R

Chemical science 20200519 23

The search is on for effective specific inhibitors for PI3Kα mutants. PI3Kα, a critical lipid kinase, has two subunits, catalytic and inhibitory. PIK3CA, the gene that encodes the p110α catalytic subunit is a highly mutated protein in cancer. Dysregulation of PI3Kα signalling is commonly associated with tumorigenesis and drug resistance. Despite its vast importance, only recently the FDA approved the first drug (alpelisib by Novartis) for breast cancer. A second (GDC0077), classified as PI3Kα is ...[more]

PMID: 32953006

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Project description:We have studied the tumor genomic evolution in a patient with metastatic breast cancer bearing an activating PIK3CA mutation. The patient was treated with the PI3Kα inhibitor BYL719 and achieved a lasting clinical response on BYL719, but eventually progressed to treatment and died shortly thereafter. A rapid autopsy was performed and a total of 14 metastatic lesions were collected for further analysis. In order to identify possible genetic determinants of acquired resistance to PI3Kα inhibition, we took a three-step approach. First, we examined both the primary tumor (before BYL719 treatment) and the new lung metastasis by whole genome sequencing (DNA from the spleen was used as a normal control). Then, we analyzed the primary tumor, lung metastasis, and the peri-aortic lesion that remained stable (responding) at the time of progression to BYL719 therapy by whole exome sequencing. Finally, to confirm and expand our findings, we sequenced the primary tumor and all the metastatic lesions to >500-fold coverage using a custom targeted deep-sequencing assay, MSK-IMPACT. Using this 3-step approach, we have demonstrated that patient’s lesion underwent parallel genetic evolution at multiple metastatic sites with different PTEN genomic alterations leading to a convergent PTEN- null phenotype resistant to PI3Kα inhibition. In order to expand our observations, we analyzed paired samples (pre-treatment and at progression) from six additional patients enrolled in the BYL719 trial. Acquired bi-allelic loss of PTEN was found in one additional patient treated with BYL719 whereas in two patients PIK3CA mutations present in the primary tumor were no longer detected at the time of progression. To functionally characterize our findings, inducible PTEN knockdown in sensitive cells resulted in resistance to BYL719, while simultaneous PI3K-p110β blockade reverted this resistance phenotype, both in cell lines and in PTEN-null xenografts derived from our patient. We conclude that parallel genetic evolution of separate sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI3Kα inhibition.

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PI3K inhibitors: review and new strategies.

Publications

PI3K inhibitors: review and new strategies.

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