Reference Detail

Ref Type

Journal Article

PMID

(36900375)

Authors

Boyd DC, Zboril EK, Olex AL, Leftwich TJ, Hairr NS, Byers HA, Valentine AD, Altman JE, Alzubi MA, Grible JM, Turner SA, Ferreira-Gonzalez A, Dozmorov MG, Harrell JC

Title

Discovering Synergistic Compounds with BYL-719 in PI3K Overactivated Basal-like PDXs.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancers	15	5	2023 Mar 03		Cancers (Basel)

URL

Abstract Text

Basal-like triple-negative breast cancer (TNBC) tumor cells are difficult to eliminate due to resistance mechanisms that promote survival. While this breast cancer subtype has low PIK3CA mutation rates when compared to estrogen receptor-positive (ER+) breast cancers, most basal-like TNBCs have an overactive PI3K pathway due to gene amplification or high gene expression. BYL-719 is a PIK3CA inhibitor that has been found to have low drug-drug interactions, which increases the likelihood that it could be useful for combinatorial therapy. Alpelisib (BYL-719) with fulvestrant was recently approved for treating ER+ breast cancer patients whose cancer had developed resistance to ER-targeting therapy. In these studies, a set of basal-like patient-derived xenograft (PDX) models was transcriptionally defined with bulk and single-cell RNA-sequencing and clinically actionable mutation profiles defined with Oncomine mutational profiling. This information was overlaid onto therapeutic drug screening results. BYL-719-based, synergistic two-drug combinations were identified with 20 different compounds, including everolimus, afatinib, and dronedarone, which were also found to be effective at minimizing tumor growth. These data support the use of these drug combinations towards cancers with activating PIK3CA mutations/gene amplifications or PTEN deficient/PI3K overactive pathways.

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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

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

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 H1047R	estrogen-receptor positive breast cancer	predicted - sensitive	Alpelisib + Everolimus	Preclinical - Patient cell culture	Actionable	In a preclinical study, combination treatment with Piqray (albelisib) and Afinitor (everolimus) synergistically inhibited cell viability of patient-derived ESR1 (ER)-positive breast cancer cells harboring PIK3CA H1047R and ESR1 (ER alpha) Y537S in culture (PMID: 36900375).	36900375
PIK3CA H1047R	estrogen-receptor positive breast cancer	predicted - sensitive	Afatinib + Alpelisib	Preclinical - Patient cell culture	Actionable	In a preclinical study, combination treatment with Piqray (albelisib) and Gilotrif (afatinib) synergistically inhibited cell viability of patient-derived ESR1 (ER)-positive breast cancer cells harboring PIK3CA H1047R and ESR1 (ER alpha) Y537S in culture (PMID: 36900375).	36900375
PTEN dec exp	triple-receptor negative breast cancer	predicted - sensitive	Alpelisib + Everolimus	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, combination treatment with Piqray (albelisib) and Afinitor (everolimus) synergistically inhibited cell viability of PTEN-deficient triple-negative breast cancer patient-derived cells in culture, and led to inhibition of tumor growth in patient-derived xenograft (PDX) models (PMID: 36900375).	36900375
PIK3CA amp PTEN H123P	triple-receptor negative breast cancer	predicted - sensitive	Alpelisib + Everolimus	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, combination treatment with Piqray (albelisib) and Afinitor (everolimus) synergistically inhibited cell viability of patient-derived triple-negative breast cancer cells harboring PIK3CA amplification and PTEN H123P in culture, and led to inhibition of tumor growth in a patient-derived xenograft (PDX) model (PMID: 36900375).	36900375
PIK3CA E545K	estrogen-receptor positive breast cancer	predicted - sensitive	Afatinib + Alpelisib	Preclinical - Patient cell culture	Actionable	In a preclinical study, combination treatment with Piqray (albelisib) and Gilotrif (afatinib) synergistically inhibited cell viability of patient-derived ESR1 (ER)-positive breast cancer cells harboring PIK3CA E545K in culture (PMID: 36900375).	36900375
PIK3CA amp PTEN H123P	triple-receptor negative breast cancer	predicted - sensitive	Afatinib + Alpelisib	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, combination treatment with Piqray (albelisib) and Gilotrif (afatinib) synergistically inhibited cell viability of patient-derived triple-negative breast cancer cells harboring PIK3CA amplification and PTEN H123P in culture, and led to inhibition of tumor growth in a patient-derived xenograft (PDX) model (PMID: 36900375).	36900375
PIK3CA E545K	estrogen-receptor positive breast cancer	predicted - sensitive	Alpelisib + Everolimus	Preclinical - Patient cell culture	Actionable	In a preclinical study, combination treatment with Piqray (albelisib) and Afinitor (everolimus) inhibited cell viability of patient-derived ESR1 (ER)-positive breast cancer cells harboring PIK3CA E545K in culture (PMID: 36900375).	36900375