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Ref Type Journal Article
PMID (32439931)
Authors Kostaras E, Kaserer T, Lazaro G, Heuss SF, Hussain A, Casado P, Hayes A, Yandim C, Palaskas N, Yu Y, Schwartz B, Raynaud F, Chung YL, Cutillas PR, Vivanco I
Title A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity.
Journal Vol Issue Date Pages Journal Short Title
British journal of cancer 123 4 2020 08 542-555 Br J Cancer
URL
Abstract Text AKT, a critical effector of the phosphoinositide 3-kinase (PI3K) signalling cascade, is an intensely pursued therapeutic target in oncology. Two distinct classes of AKT inhibitors have been in clinical development, ATP-competitive and allosteric. Class-specific differences in drug activity are likely the result of differential structural and conformational requirements governing efficient target binding, which ultimately determine isoform-specific potency, selectivity profiles and activity against clinically relevant AKT mutant variants.We have carried out a systematic evaluation of clinical AKT inhibitors using in vitro pharmacology, molecular profiling and biochemical assays together with structural modelling to better understand the context of drug-specific and drug-class-specific cell-killing activity.Our data demonstrate clear differences between ATP-competitive and allosteric AKT inhibitors, including differential effects on non-catalytic activity as measured by a novel functional readout. Surprisingly, we found that some mutations can cause drug resistance in an isoform-selective manner despite high structural conservation across AKT isoforms. Finally, we have derived drug-class-specific phosphoproteomic signatures and used them to identify effective drug combinations.These findings illustrate the utility of individual AKT inhibitors, both as drugs and as chemical probes, and the benefit of AKT inhibitor pharmacological diversity in providing a repertoire of context-specific therapeutic options.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
KU-57788 KU-57788 0 0
OSU-T315 OSU-T315 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
KU-57788 KU57788|KU 57788 DNA_PK Inhibitor 9 KU-57788 is an inhibitor of DNA-PK, potentially inducing tumor cell death (PMID: 32439931).
OSU-T315 OSUT315|OSU T315 OSU-T315 is an ILK inhibitor potentially inhibiting Akt signaling and inducing tumor cell cytotoxicity (PMID: 32439931, PMID: 25293770).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA E545K breast cancer sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) treatment inhibited Akt signaling, induced cell death, and inhibited proliferation of breast cancer cell lines harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive GSK2334470 + Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, GSK2334470 and Ipatasertib (GDC0068) combination treatment increased cell death compared to Ipatasertib (GDC0068) alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA K111N breast cancer sensitive AZD0156 + Miransertib Preclinical - Cell culture Actionable In a preclinical study, AZD0156 and Miransertib (ARQ092) combination treatment increased cell death compared to Miransertib (ARQ092) alone in a breast cancer cell line harboring PIK3CA K111N in culture (PMID: 32439931). 32439931
PIK3CA C420R breast cancer predicted - sensitive GSK690693 Preclinical - Cell culture Actionable In a preclinical study, GSK690693 treatment did not increase cell death but inhibited proliferation of a breast cancer cell line harboring PIK3CA C420R in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive AZD0156 + Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, AZD0156 and Ipatasertib (GDC-0068) combination treatment increased cell death compared to Ipatasertib (GDC-0068) alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA K111N breast cancer sensitive GSK2334470 + Miransertib Preclinical - Cell culture Actionable In a preclinical study, GSK2334470 and Miransertib (ARQ092) combination treatment increased cell death compared to Miransertib (ARQ092) alone in a breast cancer cell line harboring PIK3CA K111N in culture (PMID: 32439931). 32439931
PIK3CA K111N breast cancer predicted - sensitive GSK690693 Preclinical - Cell culture Actionable In a preclinical study, GSK690693 treatment did not increase cell death but inhibited proliferation of a breast cancer cell line harboring PIK3CA K111N in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive KU-57788 + MK2206 Preclinical - Cell culture Actionable In a preclinical study, KU-57788 and MK2206 combination treatment increased cell death compared to MK2206 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive GSK690693 Preclinical - Cell culture Actionable In a preclinical study, GSK690693 treatment inhibited Akt signaling, induced cell death, and inhibited proliferation of breast cancer cell lines harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA H1047R breast cancer predicted - sensitive GSK690693 Preclinical - Cell culture Actionable In a preclinical study, GSK690693 treatment did not increase cell death but inhibited proliferation of breast cancer cells harboring PIK3CA H1047R in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive GSK690693 + Torin 1 Preclinical - Cell culture Actionable In a preclinical study, Torin 1 and GSK690693 combination treatment increased cell death compared to GSK690693 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive GSK690693 + KU-57788 Preclinical - Cell culture Actionable In a preclinical study, KU-57788 and GSK690693 combination treatment increased cell death compared to GSK690693 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA P449T colorectal cancer sensitive ARQ 751 Preclinical - Cell culture Actionable In a preclinical study, ARQ 751 treatment induced cell death and inhibited proliferation of a colorectal cancer cell line harboring PIK3CA P449T in culture (PMID: 32439931). 32439931
PIK3CA P449T colorectal cancer predicted - sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) treatment did not increase cell death but inhibited proliferation of a breast cancer cell line harboring PIK3CA P449T in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive AZD0156 + MK2206 Preclinical - Cell culture Actionable In a preclinical study, AZD0156 and MK2206 combination treatment increased cell death compared to MK2206 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive ARQ 751 + Torin 1 Preclinical - Cell culture Actionable In a preclinical study, Torin 1 and ARQ 751 combination treatment increased cell death compared to ARQ 751 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive Ipatasertib + Sirolimus Preclinical - Cell culture Actionable In a preclinical study, Rapamune (sirolimus) and Ipatasertib (GDC0068) combination treatment increased cell death compared to Ipatasertib (GDC0068) alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive GSK2334470 + GSK690693 Preclinical - Cell culture Actionable In a preclinical study, GSK2334470 and GSK690693 combination treatment increased cell death compared to GSK690693 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA K111N breast cancer sensitive MK2206 Preclinical - Cell culture Actionable In a preclinical study, MK2206 treatment increased cell death and inhibited proliferation of a breast cancer cell line harboring PIK3CA K111N in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive GSK690693 + Sirolimus Preclinical - Cell culture Actionable In a preclinical study, Rapamune (sirolimus) and GSK690693 combination treatment increased cell death compared to GSK690693 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive KU-57788 + Miransertib Preclinical - Cell culture Actionable In a preclinical study, KU-57788 and Miransertib (ARQ092) combination treatment increased cell death compared to Miransertib (ARQ092) alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA C420R breast cancer predicted - sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) treatment did not increase cell death but inhibited proliferation of a breast cancer cell line harboring PIK3CA C420R in culture (PMID: 32439931). 32439931
PIK3CA C420R breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, Miransertib (ARQ092) treatment induced cell death and inhibited proliferation of a breast cancer cell line harboring PIK3CA C420R in culture (PMID: 32439931). 32439931
PTEN L108R breast cancer sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) treatment increased cell death and inhibited proliferation of a breast cancer cell line harboring PTEN L108R in culture (PMID: 32439931). 32439931
PIK3CA H1047R breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, Miransertib (ARQ092) treatment did not increase cell death but inhibited proliferation of breast cancer cells harboring PIK3CA H1047R in culture (PMID: 32439931). 32439931
PIK3CA E542K stomach cancer sensitive MK2206 Preclinical - Cell culture Actionable In a preclinical study, MK2206 treatment induced cell death and inhibited proliferation of a gastric cancer cell line harboring PIK3CA E542K in culture (PMID: 32439931). 32439931
PIK3CA H1047R breast cancer sensitive ARQ 751 Preclinical - Cell culture Actionable In a preclinical study, ARQ 751 treatment did not increase cell death but inhibited proliferation of breast cancer cells harboring PIK3CA H1047R in culture (PMID: 32439931). 32439931
PIK3CA K111N breast cancer sensitive Miransertib + OSU-T315 Preclinical - Cell culture Actionable In a preclinical study, OSU-T315 and Miransertib (ARQ092) combination treatment increased cell death compared to Miransertib (ARQ092) alone in a breast cancer cell line harboring PIK3CA K111N in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive ARQ 751 + OSU-T315 Preclinical - Cell culture Actionable In a preclinical study, OSU-T315 and ARQ 751combination treatment increased cell death compared to ARQ 751 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive ARQ 751 + AZD0156 Preclinical - Cell culture Actionable In a preclinical study, AZD0156 and ARQ 751 combination treatment increased cell death compared to ARQ 751 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA K111N breast cancer predicted - sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) treatment did not increase cell death but inhibited proliferation of a breast cancer cell line harboring PIK3CA K111N in culture (PMID: 32439931). 32439931
PTEN L108R breast cancer sensitive MK2206 Preclinical - Cell culture Actionable In a preclinical study, MK2206 treatment increased cell death and inhibited proliferation of a breast cancer cell line harboring PTEN L108R in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive Ipatasertib + KU-57788 Preclinical - Cell culture Actionable In a preclinical study, KU-57788 and Ipatasertib (GDC-0068) combination treatment increased cell death compared to Ipatasertib (GDC-0068) alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA P449T colorectal cancer sensitive GSK690693 Preclinical - Cell culture Actionable In a preclinical study, GSK690693 treatment induced cell death and inhibited proliferation of a colorectal cancer cell line harboring PIK3CA P449T in culture (PMID: 32439931). 32439931
PTEN L108R breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, Miransertib (ARQ092) treatment increased cell death and inhibited proliferation of a breast cancer cell line harboring PTEN L108R in culture (PMID: 32439931). 32439931
PIK3CA E542K stomach cancer predicted - sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) treatment did not increase cell death but inhibited proliferation of a gastric cancer cell line harboring PIK3CA E542K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive ARQ 751 + GSK2334470 Preclinical - Cell culture Actionable In a preclinical study, GSK2334470 and ARQ 751 combination treatment increased cell death compared to ARQ 751 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer decreased response LAM-002A + MK2206 Preclinical - Cell culture Actionable In a preclinical study, LAM-002A (Apilimod dimesylate) and MK2206 combination treatment resulted in less cell death compared to MK2206 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA K111N breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, Miransertib (ARQ092) treatment induced cell death and inhibited proliferation of a breast cancer cell line harboring PIK3CA K111N in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive GSK2334470 + Miransertib Preclinical - Cell culture Actionable In a preclinical study, GSK2334470 and Miransertib (ARQ092) combination treatment increased cell death compared to Miransertib (ARQ092) alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive GSK690693 + OSU-T315 Preclinical - Cell culture Actionable In a preclinical study, OSU-T315 and GSK690693 combination treatment increased cell death compared to GSK690693 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive MK2206 Preclinical - Cell culture Actionable In a preclinical study, MK2206 treatment inhibited Akt signaling, induced cell death, and inhibited proliferation of breast cancer cell lines harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA C420R breast cancer sensitive MK2206 Preclinical - Cell culture Actionable In a preclinical study, MK2206 treatment induced cell death and inhibited proliferation of a breast cancer cell line harboring PIK3CA C420R in culture (PMID: 32439931). 32439931
PIK3CA C420R breast cancer sensitive ARQ 751 Preclinical - Cell culture Actionable In a preclinical study, ARQ 751 treatment induced cell death and inhibited proliferation of a breast cancer cell line harboring PIK3CA C420R in culture (PMID: 32439931). 32439931
PIK3CA H1047R breast cancer predicted - sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) treatment did not increase cell death but inhibited proliferation of breast cancer cells harboring PIK3CA H1047R in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive Miransertib + Torin 1 Preclinical - Cell culture Actionable In a preclinical study, Torin 1 and Miransertib (ARQ092) combination treatment increased cell death compared to Miransertib (ARQ092) alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive AZD0156 + GSK690693 Preclinical - Cell culture Actionable In a preclinical study, AZD0156 and GSK690693 combination treatment increased cell death compared to GSK690693 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E542K stomach cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, Miransertib (ARQ092) treatment induced cell death and inhibited proliferation of a gastric cancer cell line harboring PIK3CA E542K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive ARQ 751 + Sirolimus Preclinical - Cell culture Actionable In a preclinical study, Rapamune (sirolimus) and ARQ 751 combination treatment increased cell death compared to ARQ 751 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive AZD0156 + Miransertib Preclinical - Cell culture Actionable In a preclinical study, AZD0156 and Miransertib (ARQ092) combination treatment increased cell death compared to Miransertib (ARQ092) alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive GSK2334470 + MK2206 Preclinical - Cell culture Actionable In a preclinical study, GSK2334470 and MK2206 combination treatment increased cell death compared to MK2206 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer decreased response ARQ 751 + LAM-002A Preclinical - Cell culture Actionable In a preclinical study, LAM-002A (Apilimod dimesylate) and ARQ 751 combination treatment resulted in less cell death compared to ARQ 751 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA H1047R breast cancer sensitive MK2206 Preclinical - Cell culture Actionable In a preclinical study, MK2206 treatment did not increase cell death but inhibited proliferation of breast cancer cells harboring PIK3CA H1047R in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive MK2206 + Sirolimus Preclinical - Cell culture Actionable In a preclinical study, Rapamune (sirolimus) and MK2206 combination treatment increased cell death compared to MK2206 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive ARQ 751 + KU-57788 Preclinical - Cell culture Actionable In a preclinical study, KU-57788 and ARQ 751 combination treatment increased cell death compared to ARQ 751 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PTEN L108R breast cancer predicted - sensitive GSK690693 Preclinical - Cell culture Actionable In a preclinical study, GSK690693 treatment did not increase cell death but inhibited proliferation of a breast cancer cell line harboring PTEN L108R in culture (PMID: 32439931). 32439931
PIK3CA E542K stomach cancer predicted - sensitive GSK690693 Preclinical - Cell culture Actionable In a preclinical study, GSK690693 treatment did not increase cell death but inhibited proliferation of a gastric cancer cell line harboring PIK3CA E542K in culture (PMID: 32439931). 32439931
PIK3CA P449T colorectal cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, Miransertib (ARQ092) treatment induced cell death and inhibited proliferation of a colorectal cancer cell line harboring PIK3CA P449T in culture (PMID: 32439931). 32439931
PIK3CA E542K stomach cancer sensitive ARQ 751 Preclinical - Cell culture Actionable In a preclinical study, ARQ 751 treatment induced cell death and inhibited proliferation of a gastric cancer cell line harboring PIK3CA E542K in culture (PMID: 32439931). 32439931
PIK3CA P449T colorectal cancer sensitive MK2206 Preclinical - Cell culture Actionable In a preclinical study, MK2206 treatment induced cell death and inhibited proliferation of a colorectal cancer cell line harboring PIK3CA P449T in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive Miransertib + OSU-T315 Preclinical - Cell culture Actionable In a preclinical study, OSU-T315 and Miransertib (ARQ092) combination treatment increased cell death compared to Miransertib (ARQ092) alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PTEN L108R breast cancer sensitive ARQ 751 Preclinical - Cell culture Actionable In a preclinical study, ARQ 751 treatment increased cell death and inhibited proliferation of a breast cancer cell line harboring PTEN L108R in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive MK2206 + Torin 1 Preclinical - Cell culture Actionable In a preclinical study, Torin 1 and MK2206 combination treatment increased cell death compared to MK2206 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive Miransertib + Sirolimus Preclinical - Cell culture Actionable In a preclinical study, Rapamune (sirolimus) and Miransertib (ARQ092) combination treatment increased cell death compared to Miransertib (ARQ092) alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive Ipatasertib + Torin 1 Preclinical - Cell culture Actionable In a preclinical study, Torin 1 and Ipatasertib (GDC0068) combination treatment increased cell death compared to Ipatasertib (GDC0068) alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, Miransertib (ARQ092) treatment inhibited Akt signaling, induced cell death, and inhibited proliferation of breast cancer cell lines harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive MK2206 + OSU-T315 Preclinical - Cell culture Actionable In a preclinical study, OSU-T315 and MK2206 combination treatment increased cell death compared to MK2206 alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive ARQ 751 Preclinical - Cell culture Actionable In a preclinical study, ARQ 751 treatment inhibited Akt signaling, induced cell death, and inhibited proliferation of breast cancer cell lines harboring PIK3CA E545K in culture (PMID: 32439931). 32439931
PIK3CA K111N breast cancer sensitive ARQ 751 Preclinical - Cell culture Actionable In a preclinical study, ARQ 751 treatment did not increase cell death but inhibited proliferation of a breast cancer cell line harboring PIK3CA K111N in culture (PMID: 32439931). 32439931
PIK3CA K111N breast cancer sensitive Ipatasertib + OSU-T315 Preclinical - Cell culture Actionable In a preclinical study, OSU-T315 and Ipatasertib (GDC0068) combination treatment increased cell death compared to Ipatasertib (GDC0068) alone in a breast cancer cell line harboring PIK3CA K111N in culture (PMID: 32439931). 32439931
PIK3CA K111N breast cancer sensitive KU-57788 + Miransertib Preclinical - Cell culture Actionable In a preclinical study, KU-57788 and Miransertib (ARQ092) combination treatment increased cell death compared to Miransertib (ARQ092) alone in a breast cancer cell line harboring PIK3CA K111N in culture (PMID: 32439931). 32439931
PIK3CA E545K breast cancer sensitive Ipatasertib + OSU-T315 Preclinical - Cell culture Actionable In a preclinical study, OSU-T315 and Ipatasertib (GDC0068) combination treatment increased cell death compared to Ipatasertib (GDC0068) alone in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 32439931). 32439931