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Oncogenic activation of the PI3-kinase p110β isoform via the tumor-derived PIK3CβD1067V kinase domain mutation

Oncogene volume 35, pages 1198–1205 (2016)Cite this article

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Abstract

Activation of the phosphoinositide 3-kinase (PI3K) pathway occurs widely in human cancers. Although somatic mutations in the PI3K pathway genes PIK3CA and PTEN are known to drive PI3K pathway activation and cancer growth, the significance of somatic mutations in other PI3K pathway genes is less clear. Here, we establish the signaling and oncogenic properties of a recurrent somatic mutation in the PI3K p110β isoform that resides within its kinase domain (PIK3CβD1067V). We initially observed PIK3CβD1067V by exome sequencing analysis of an EGFR-mutant non-small cell lung cancer (NSCLC) tumor biopsy from a patient with acquired erlotinib resistance. On the basis of this finding, we hypothesized that PIK3CβD1067V might function as a novel tumor-promoting genetic alteration, and potentially an oncogene, in certain cancers. Consistent with this hypothesis, analysis of additional tumor exome data sets revealed the presence of PIK3CβD1067V at low frequency in other patient tumor samples (including renal cell carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, melanoma, thyroid carcinoma and endometrial carcinoma). Functional studies revealed that PIK3CβD1067V promoted PI3K pathway signaling, enhanced cell growth in vitro, and was sufficient for tumor formation in vivo. Pharmacologic inhibition of PIK3Cβ with TGX-221 (isoform-selective p110β inhibitor) specifically suppressed growth in patient-derived renal-cell carcinoma cells with endogenous PIK3CβD1067V and in NIH-3T3 and human EGFR-mutant lung adenocarcinoma cells engineered to express this mutant PI3K. In the EGFR-mutant lung adenocarcinoma cells, expression of PIK3CβD1067V also promoted erlotinib resistance. Our data establish a novel oncogenic form of PI3K, revealing the signaling and oncogenic properties of PIK3CβD1067V and its potential therapeutic relevance in cancer. Our findings provide new insight into the genetic mechanisms underlying PI3K pathway activation in human tumors and indicate that PIK3CβD1067V is a rational therapeutic target in certain cancers.

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Acknowledgements

We acknowledge funding support (to TGB) from the following sources: NIH Director's New Innovator Award, Howard Hughes Medical Institute, Doris Duke Charitable Foundation, American Lung Association, National Lung Cancer Partnership, Sidney Kimmel Foundation for Cancer Research and Searle Scholars Program.

Author Contributions

EP designed, conducted and analyzed all experiments; PG, JSJ, MAG, JW, WP and TGB analyzed the patient tumor sequencing data; GH conducted shRNA knockdown experiments; VRO conducted tumor xenografts; RB provided patient tumor samples; TGB designed and analyzed the experiments; EP and TGB wrote the manuscript with input from all authors.

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology and Oncology, University of California, San Francisco, CA, USA

    E Pazarentzos, G Hrustanovic, V R Olivas, M A Gubens & T G Bivona

  2. Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA

    E Pazarentzos, G Hrustanovic, V R Olivas, M A Gubens & T G Bivona

  3. Driver Group, San Francisco, CA, USA

    P Giannikopoulos, J St John & W Polkinghorn

  4. Department of Pathology, University of California, San Francisco, CA, USA

    R Balassanian

  5. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA

    J Weissman

  6. Howard Hughes Medical Institute, University of California, San Francisco, CA, USA

    J Weissman

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  1. E Pazarentzos
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  2. P Giannikopoulos
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  8. J Weissman
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  10. T G Bivona
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Corresponding author

Correspondence to T G Bivona.

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Competing interests

TGB is a consultant to Driver Group, Novartis, Clovis Oncology and Cleave Biosciences, and has received a research grant from Servier; JW is a consultant to Driver Group; PG, JSJ and WP are employees of Driver Group. The remaining authors declare no conflict of interest.

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Pazarentzos, E., Giannikopoulos, P., Hrustanovic, G. et al. Oncogenic activation of the PI3-kinase p110β isoform via the tumor-derived PIK3CβD1067V kinase domain mutation. Oncogene 35, 1198–1205 (2016). https://doi.org/10.1038/onc.2015.173

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  • DOI: https://doi.org/10.1038/onc.2015.173

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