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Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3K? inhibitors.

ABSTRACT: Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3K?) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed PIK3CA-mutant cancer genomes and observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double PIK3CA mutations are in cis on the same allele and result in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110? binding to the inhibitory subunit p85?, which relieves its catalytic inhibition, and increased p110? membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3K? inhibitors compared with single-hotspot mutations.

SUBMITTER: Vasan N

PROVIDER: S-EPMC7173400 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors.

Vasan Neil N Razavi Pedram P Johnson Jared L JL Shao Hong H Shah Hardik H Antoine Alesia A Ladewig Erik E Gorelick Alexander A Lin Ting-Yu TY Toska Eneda E Xu Guotai G Kazmi Abiha A Chang Matthew T MT Taylor Barry S BS Dickler Maura N MN Jhaveri Komal K Chandarlapaty Sarat S Rabadan Raul R Reznik Ed E Smith Melissa L ML Sebra Robert R Schimmoller Frauke F Wilson Timothy R TR Friedman Lori S LS Cantley Lewis C LC Scaltriti Maurizio M Baselga José J

Science (New York, N.Y.) 20191101 6466

Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Kα) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed PIK3CA-mutant cancer genomes and observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double PIK3CA mutations are in cis on the same allele and result ...[more]

PMID: 31699932

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Project description:INTRODUCTION:Triple negative breast cancer (TNBC) is a heterogeneous collection of biologically diverse cancers, which contributes to variable clinical outcomes. Previously, we identified a TNBC subtype that has a luminal phenotype and expresses the androgen receptor (AR+). TNBC cells derived from these luminal AR + tumors have high frequency phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations. The purpose of this study was to determine if targeting phosphoinositide 3-kinase (PI3K) alone or in combination with an AR antagonist is effective in AR + TNBC. METHODS:We determined the frequency of activating PIK3CA mutations in AR + and AR- TNBC clinical cases. Using AR?+?TNBC cell line and xenograft models we evaluated the effectiveness of PI3K inhibitors, used alone or in combination with an AR antagonist, on tumor cell growth and viability. RESULTS:PIK3CA kinase mutations were highly clonal, more frequent in AR + vs. AR- TNBC (40% vs. 4%), and often associated with concurrent amplification of the PIK3CA locus. PI3K/mTOR inhibitors had an additive growth inhibitory effect when combined with genetic or pharmacological AR targeting in AR + TNBC cells. We also analyzed the combination of bicalutamide +/- the pan-PI3K inhibitor GDC-0941 or the dual PI3K/mTOR inhibitor GDC-0980 in xenograft tumor studies and observed additive effects. CONCLUSIONS:While approximately one third of TNBC patients respond to neoadjuvant/adjuvant chemotherapy, recent studies have shown that patients with AR + TNBC are far less likely to benefit from the current standard of care chemotherapy regimens and novel targeted approaches need to be investigated. In this study, we show that activating PIK3CA mutations are enriched in AR?+?TNBC; and, we show that the growth and viability of AR + TNBC cell line models is significantly reduced after treatment with PI3K inhibitors used in combination with an AR antagonist. These results provide rationale for pre-selection of TNBC patients with a biomarker (AR expression) to investigate the use of AR antagonists in combination with PI3K/mTOR inhibitors.

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Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3K? inhibitors.

Publications

Double <i>PIK3CA</i> mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors.

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