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Ref Type Journal Article
PMID (37916958)
Authors Varkaris A, Fece de la Cruz F, Martin EE, Norden BL, Chevalier N, Kehlmann AM, Leshchiner I, Barnes H, Ehnstrom S, Stavridi AM, Yuan X, Kim JS, Ellis H, Papatheodoridi A, Gunaydin H, Danysh BP, Parida L, Sanidas I, Ji Y, Lau K, Wulf GM, Bardia A, Spring LM, Isakoff SJ, Lennerz JK, Pierce L, Pazolli E, Getz G, Corcoran RB, Juric D
Title Allosteric PI3K-alpha inhibition overcomes on-target resistance to orthosteric inhibitors mediated by secondary PIK3CA mutations.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 2023 Nov 02 Cancer Discov
URL
Abstract Text PIK3CA mutations occur in ~8% of cancers, including ~40% of HR-positive breast cancers, where the PI3K-alpha (PI3Ka)-selective inhibitor alpelisib is FDA-approved in combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as PTEN loss, clinical acquired resistance to PI3Ka inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies in 39 patients with advanced breast cancer developing acquired resistance to PI3Ka-inhibitors, we observe that 50% of patients acquire genomic alterations within the PI3K-pathway, including PTEN loss and activating AKT1 mutations. Notably, while secondary PIK3CA mutations were previously reported to increase sensitivity to PI3Ka-inhibitors, we identified emergent secondary resistance mutations in PIK3CA that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Ka-selective vs. pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Ka-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers.

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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
FGFR2 T319I missense unknown FGFR2 T319I lies within Ig-like C2-type domain 3 of the Fgfr2 protein (UniProt.org). T319I has been identified in sequencing studies (PMID: 37916958), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Nov 2024).
PIK3CA E172Q missense unknown PIK3CA E172Q does not lie within any known functional domains of the Pik3ca protein (UniProt.org). E172Q has been identified in sequencing studies (PMID: 37916958), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Jan 2024).
PIK3CA E737Q missense unknown PIK3CA E737Q does not lie within any known functional domains of the Pik3ca protein (UniProt.org). E737Q has been identified in sequencing studies (PMID: 37916958), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Jan 2024).
PIK3CA I197K missense unknown PIK3CA I197K lies within the PI3K-RBD domain of the Pik3ca protein (UniProt.org). I197K has been identified in sequencing studies (PMID: 37916958), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Jan 2024).
PIK3CA I817F missense unknown PIK3CA I817F lies within the PI3K/PI4K catalytic domain of the Pik3ca protein (UniProt.org). I817F has been identified in the scientific literature (PMID: 37916958), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Dec 2023).
PIK3CA Q859H missense unknown PIK3CA Q859H lies within the PI3K/PI4K catalytic domain of the Pik3ca protein (UniProt.org). Q859H has been associated with resistance to PI3K inhibitors in culture (PMID: 37916958), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Dec 2023). Y
PIK3CA Q859K missense unknown PIK3CA Q859K lies within the PI3K/PI4K catalytic domain of the Pik3ca protein (UniProt.org). Q859K has been associated with resistance to PI3K inhibitors in culture (PMID: 37916958), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Dec 2023). Y
PIK3CA W780R missense unknown PIK3CA W780R lies within the PI3K/PI4K catalytic domain of the Pik3ca protein (UniProt.org). W780R has been associated with resistance to PI3K inhibitors in culture (PMID: 37916958), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Dec 2023). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA E545K PIK3CA E726K breast cancer sensitive Inavolisib Preclinical - Cell culture Actionable In a preclinical study, Itovebi (inavolisib) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA E726K in culture (PMID: 37916958). 37916958
PIK3CA W780R PIK3CA H1047R breast cancer resistant Inavolisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA W780R was resistant to Itovebi (inavolisib) in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA Q859H breast cancer sensitive Taselisib Preclinical - Cell culture Actionable In a preclinical study, Taselisib (GDC-0032) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA Q859H in culture (PMID: 37916958). 37916958
FGFR2 T319I PIK3CA N345K PIK3CA E453K Her2-receptor negative breast cancer predicted - resistant Inavolisib Case Reports/Case Series Actionable In a clinical case study, FGFR2 T319I was identified in circulating tumor DNA at the time of progression on Itovebi (inavolisib) in a patient with ESR1-positive, ERBB2 (HER2)-negative breast cancer harboring PIK3CA N345K and E453K (PMID: 37916958). 37916958
PIK3CA I817F PIK3CA H1047R breast cancer sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA I817F in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA I817F breast cancer sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA I817F in culture (PMID: 37916958). 37916958
PIK3CA Q859K PIK3CA H1047R breast cancer sensitive RLY-2608 Preclinical - Cell culture Actionable In a preclinical study, RLY-2608 inhibited downstream signaling and viability in a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA Q859K in culture (PMID: 37916958). 37916958
PIK3CA Q859K PIK3CA H1047R breast cancer sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA Q859K in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA Q859H breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, Miransertib (ARQ092) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA Q859H in culture (PMID: 37916958). 37916958
PIK3CA I817F PIK3CA H1047R breast cancer sensitive Alpelisib Preclinical - Cell culture Actionable In a preclinical study, Piqray (alpelisib) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA I817F in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA W780R breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, Miransertib (ARQ092) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA W780R in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA W780R breast cancer resistant Inavolisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA W780R was resistant to Itovebi (inavolisib) in culture (PMID: 37916958). 37916958
PIK3CA Q859H PIK3CA H1047R breast cancer sensitive Pictilisib Preclinical - Cell culture Actionable In a preclinical study, Pictilisib (GDC-0941) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA Q859H in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA Q859H breast cancer sensitive Pictilisib Preclinical - Cell culture Actionable In a preclinical study, Pictilisib (GDC-0941) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA Q859H in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA W780R breast cancer sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA W780R in culture (PMID: 37916958). 37916958
PIK3CA Q859K PIK3CA H1047R breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, Miransertib (ARQ092) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA Q859K in culture (PMID: 37916958). 37916958
PIK3CA Q859H PIK3CA H1047R breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, Miransertib (ARQ092) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA Q859H in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA E726K breast cancer sensitive Taselisib Preclinical - Cell culture Actionable In a preclinical study, Taselisib (GDC-0032) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA E726K in culture (PMID: 37916958). 37916958
PIK3CA W780R PIK3CA H1047R breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, Miransertib (ARQ092) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA W780R in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA Q859H breast cancer resistant Inavolisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA Q859H was resistant to Itovebi (inavolisib) in culture (PMID: 37916958). 37916958
PIK3CA E726K PIK3CA H1047R breast cancer sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA E726K in culture (PMID: 37916958). 37916958
PIK3CA Q859K PIK3CA H1047R breast cancer resistant Taselisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA Q859K was resistant to Taselisib (GDC-0032) in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA W780R breast cancer resistant Taselisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA W780R was resistant to Taselisib (GDC-0032) in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA Q859H breast cancer sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA Q859H in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA E726K breast cancer sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA E726K in culture (PMID: 37916958). 37916958
PIK3CA W780R PIK3CA H1047R breast cancer sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA W780R in culture (PMID: 37916958). 37916958
PIK3CA W780R PIK3CA H1047R breast cancer resistant Taselisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA W780R was resistant to Taselisib (GDC-0032) in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA I817F breast cancer sensitive Pictilisib Preclinical - Cell culture Actionable In a preclinical study, Pictilisib (GDC-0941) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA I817F in culture (PMID: 37916958). 37916958
PIK3CA Q859K PIK3CA H1047R breast cancer resistant Inavolisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA Q859K was resistant to Itovebi (inavolisib) in culture (PMID: 37916958). 37916958
PIK3CA Q859H PIK3CA H1047R breast cancer resistant Alpelisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA Q859H was resistant to Piqray (alpelisib) in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA I817F breast cancer sensitive Taselisib Preclinical - Cell culture Actionable In a preclinical study, Taselisib (GDC-0032) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA I817F in culture (PMID: 37916958). 37916958
PIK3CA E726K PIK3CA H1047R breast cancer resistant Pictilisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA E726K was resistant to Pictilisib (GDC-0941) in culture (PMID: 37916958). 37916958
PIK3CA E726K PIK3CA H1047R breast cancer sensitive Alpelisib Preclinical - Biochemical Actionable In a preclinical study, Piqray (alpelisib) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA E726K in culture (PMID: 37916958). 37916958
PIK3CA Q859H PIK3CA H1047R breast cancer resistant Taselisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA Q859H was resistant to Taselisib (GDC-0032) in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA E726K breast cancer sensitive Alpelisib Preclinical - Cell culture Actionable In a preclinical study, Piqray (alpelisib) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA E726K in culture (PMID: 37916958). 37916958
PIK3CA I817F PIK3CA H1047R breast cancer sensitive Pictilisib Preclinical - Cell culture Actionable In a preclinical study, Pictilisib (GDC-0941) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA I817F in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA I817F breast cancer sensitive Alpelisib Preclinical - Cell culture Actionable In a preclinical study, Piqray (alpelisib) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA I817F in culture (PMID: 37916958). 37916958
PIK3CA E726K PIK3CA H1047R breast cancer resistant Miransertib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA E726K was resistant to Miransertib (ARQ092) in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA W780R breast cancer resistant Alpelisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA W780R was resistant to Piqray (alpelisib) in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA I817F breast cancer sensitive Inavolisib Preclinical - Cell culture Actionable In a preclinical study, Itovebi (inavolisib) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA I817F in culture (PMID: 37916958). 37916958
PIK3CA E726K PIK3CA H1047R breast cancer resistant RLY-2608 Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA E726K was resistant to RLY-2608 treatment in culture (PMID: 37916958). 37916958
PIK3CA Q859K PIK3CA H1047R breast cancer resistant Alpelisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA Q859K was resistant to Piqray (alpelisib) in culture (PMID: 37916958). 37916958
PIK3CA I817F PIK3CA H1047R breast cancer sensitive Taselisib Preclinical - Cell culture Actionable In a preclinical study, Taselisib (GDC-0032) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA I817F in culture (PMID: 37916958). 37916958
PIK3CA E726K PIK3CA H1047R breast cancer sensitive Taselisib Preclinical - Cell culture Actionable In a preclinical study, Taselisib (GDC-0032) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA E726K in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA Q859H breast cancer resistant Alpelisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA Q859H was resistant to Piqray (alpelisib) in culture (PMID: 37916958). 37916958
PIK3CA Q859H PIK3CA H1047R breast cancer sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA Q859H in culture (PMID: 37916958). 37916958
PIK3CA Q859H PIK3CA H1047R breast cancer sensitive RLY-2608 Preclinical - Cell culture Actionable In a preclinical study, RLY-2608 inhibited downstream signaling and viability in a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA Q859H in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA I817F breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, Miransertib (ARQ092) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA I817F in culture (PMID: 37916958). 37916958
PIK3CA W780R PIK3CA H1047R breast cancer resistant Pictilisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA W780R was resistant to Pictilisib (GDC-0941) in culture (PMID: 37916958). 37916958
PIK3CA W780R PIK3CA H1047R breast cancer sensitive RLY-2608 Preclinical - Cell culture Actionable In a preclinical study, RLY-2608 inhibited downstream signaling and viability in a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA W780R in culture (PMID: 37916958). 37916958
PIK3CA E726K PIK3CA H1047R breast cancer sensitive Inavolisib Preclinical - Cell culture Actionable In a preclinical study, Itovebi (inavolisib) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA E726K in culture (PMID: 37916958). 37916958
PIK3CA Q859H PIK3CA H1047R breast cancer resistant Inavolisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA Q859H was resistant to Itovebi (inavolisib) in culture (PMID: 37916958). 37916958
PIK3CA I817F PIK3CA H1047R breast cancer sensitive RLY-2608 Preclinical - Cell culture Actionable In a preclinical study, RLY-2608 treatment decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA I817F in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA E726K breast cancer sensitive Pictilisib Preclinical - Cell culture Actionable In a preclinical study, Pictilisib (GDC-0941) decreased viability of a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA E726K in culture (PMID: 37916958). 37916958
PIK3CA E545K PIK3CA W780R breast cancer resistant Pictilisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA E545K and expressing PIK3CA W780R was resistant to Pictilisib (GDC-0941) in culture (PMID: 37916958). 37916958
PIK3CA Q859K PIK3CA H1047R breast cancer sensitive Pictilisib Preclinical - Cell culture Actionable In a preclinical study, Pictilisib (GDC-0941) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA Q859K in culture (PMID: 37916958). 37916958
PIK3CA I817F PIK3CA H1047R breast cancer sensitive Inavolisib Preclinical - Cell culture Actionable In a preclinical study, Itovebi (inavolisib) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA I817F in culture (PMID: 37916958). 37916958
PIK3CA W780R PIK3CA H1047R breast cancer resistant Alpelisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA W780R was resistant to Piqray (alpelisib) in culture (PMID: 37916958). 37916958
PIK3CA I817F PIK3CA H1047R breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, Miransertib (ARQ092) decreased viability of a breast cancer cell line harboring PIK3CA H1047R and expressing PIK3CA I817F in culture (PMID: 37916958). 37916958