Reference Detail

Ref Type

Journal Article

PMID

(31699932)

Authors

Vasan N, Razavi P, Johnson JL, Shao H, Shah H, Antoine A, Ladewig E, Gorelick A, Lin TY, Toska E, Xu G, Kazmi A, Chang MT, Taylor BS, Dickler MN, Jhaveri K, Chandarlapaty S, Rabadan R, Reznik E, Smith ML, Sebra R, Schimmoller F, Wilson TR, Friedman LS, Cantley LC, Scaltriti M, Baselga J

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Science (New York, N.Y.)	366	6466	2019 11 08	714-723	Science

URL

Abstract Text

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 in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased p110α membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3Kα inhibitors compared with single-hotspot mutations.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA E453Q PIK3CA H1047R	breast cancer	sensitive	Inavolisib	Preclinical - Cell culture	Actionable	In a preclinical study, breast epithelial cells expressing PIK3CA E453Q and PIK3CA H1047R in cis demonstrated increased sensitivity to growth inhibition by Itovebi (inavolisib) treatment compared to cells expressing individual PIK3CA mutations in culture (PMID: 31699932).	31699932
PIK3CA E453Q PIK3CA H1047R	breast cancer	sensitive	Alpelisib	Preclinical - Cell culture	Actionable	In a preclinical study, breast epithelial cells expressing PIK3CA E453Q and PIK3CA H1047R in cis demonstrated increased sensitivity to growth inhibition by Piqray (Alpelisib) treatment compared to cells expressing individual PIK3CA mutations in culture (PMID: 31699932).	31699932
PIK3CA E453Q PIK3CA H1047R	breast cancer	sensitive	Everolimus	Preclinical - Cell culture	Actionable	In a preclinical study, breast epithelial cells expressing PIK3CA E453Q and PIK3CA H1047R in cis demonstrated increased sensitivity to growth inhibition by Afinitor (everolimus) treatment compared to cells expressing individual PIK3CA mutations in culture (PMID: 31699932).	31699932
PIK3CA E545K PIK3CA E726K	breast cancer	sensitive	Inavolisib	Preclinical - Cell culture	Actionable	In a preclinical study, breast epithelial cells expressing PIK3CA E545K and PIK3CA E726K in cis demonstrated increased sensitivity to growth inhibition by Itovebi (inavolisib) treatment compared to cells expressing individual PIK3CA mutations in culture (PMID: 31699932).	31699932
PIK3CA E545K PIK3CA E726K	breast cancer	sensitive	Alpelisib	Preclinical - Cell culture	Actionable	In a preclinical study, breast epithelial cells expressing PIK3CA E545K and PIK3CA E726K in cis demonstrated increased sensitivity to growth inhibition by Piqray (Alpelisib) treatment compared to cells expressing individual PIK3CA mutations in culture (PMID: 31699932).	31699932
PIK3CA E545K PIK3CA E726K	breast cancer	sensitive	Everolimus	Preclinical - Cell culture	Actionable	In a preclinical study, breast epithelial cells expressing PIK3CA E545K and PIK3CA E726K in cis demonstrated increased sensitivity to growth inhibition by Afinitor (everolimus) treatment compared to cells expressing individual PIK3CA mutations in culture (PMID: 31699932).	31699932
PIK3CA E545K PIK3CA M1043L	breast cancer	sensitive	Alpelisib	Preclinical - Cell culture	Actionable	In a preclinical study, breast epithelial cells expressing PIK3CA E545K and PIK3CA M1043L in cis demonstrated increased sensitivity to growth inhibition by Piqray (Alpelisib) treatment compared to cells expressing individual PIK3CA mutations in culture (PMID: 31699932).	31699932
PIK3CA E545K PIK3CA M1043L	breast cancer	sensitive	Everolimus	Preclinical - Cell culture	Actionable	In a preclinical study, breast epithelial cells expressing PIK3CA E545K and PIK3CA M1043L in cis demonstrated increased sensitivity to growth inhibition by Afinitor (everolimus) treatment compared to cells expressing individual PIK3CA mutations in culture (PMID: 31699932).	31699932
PIK3CA E545K PIK3CA M1043L	breast cancer	sensitive	Inavolisib	Preclinical - Cell culture	Actionable	In a preclinical study, breast epithelial cells expressing PIK3CA E545K and PIK3CA M1043L in cis demonstrated increased sensitivity to growth inhibition by Itovebi (inavolisib) treatment compared to cells expressing individual PIK3CA mutations in culture (PMID: 31699932).	31699932
PIK3CA E726K PIK3CA H1047R	breast cancer	sensitive	Everolimus	Preclinical - Cell culture	Actionable	In a preclinical study, breast epithelial cells expressing PIK3CA E726K and PIK3CA H1047R in cis demonstrated increased sensitivity to growth inhibition by Afinitor (everolimus) treatment compared to cells expressing individual PIK3CA mutations in culture (PMID: 31699932).	31699932
PIK3CA E726K PIK3CA H1047R	breast cancer	sensitive	Alpelisib	Preclinical - Cell culture	Actionable	In a preclinical study, breast epithelial cells expressing PIK3CA E726K and PIK3CA H1047R in cis demonstrated increased sensitivity to growth inhibition by Piqray (Alpelisib) treatment compared to cells expressing individual PIK3CA mutations in culture, while cells expressing PIK3CA E726K and PIK3CA H1047R in trans did not (PMID: 31699932).	31699932
PIK3CA E726K PIK3CA H1047R	breast cancer	sensitive	Inavolisib	Preclinical - Cell culture	Actionable	In a preclinical study, breast epithelial cells expressing PIK3CA E726K and PIK3CA H1047R in cis demonstrated increased sensitivity to growth inhibition by Itovebi (inavolisib) treatment compared to cells expressing individual PIK3CA mutations in culture (PMID: 31699932).	31699932

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