Abstract PD4-15: A tale of two pathways: Mutations in PI3K pathway in TNBC patients matter for the oncogenic cooperation with DNA damage repair pathway
Authors: Dey N , Williams C , Krie A , Klein J , Williams K , Carlson JH , De PK , Leyland-Jones B 
Published: February 2018

Background: Mutations guide targeted therapy in the personalized medicine. In the opening chapter of our recently edited book (Dey et al., 2016), Prof. L. Cantley elegantly elucidated the basic signaling of the PI3K pathway in cancers. Mutations in the PI3K pathway are not only common and subtype-specific in BC but are also contextual. Alterations in DNA damage repair (DDR) pathway involving HRD (Homologous Recombination Defect) genes are one of the important contextual events of the upregulation of the PI3K pathway (De et al., 2016). Aim: Here we interrogated the contextuality of alterations of the PI3K and DDR pathway genes in our Avera patients. The mechanism of contextual cooperation between the pathwayswas experimentally validated. Methods: We examined mutation profile (FoundationOne) of our patients (Avera Cancer Institute) and patients fromthe TCGA data (cBioPortal). We validated the cooperation of the two pathwaysexperimentally by the synergy model of mutation-specific drugs; PI3K-PTEN-mTOR pathway inhibitor(s) and PARP inhibitor(s) using TNBC model.Results: We analyzed alterations of 17 and 12 genes of the PI3K and DDR pathways respectively in subtypes of BC. In luminal A and HER2-enriched (TCGA, Nature 2012), the alteration of PIK3CA reached 49 % and 47% as compared to 37 % in luminal B and 25% in basal-like.In the basal-like/TNBC subtype (cBioPortal) 12 DDR pathway genes (CHEK1/2, RAD51, BRCA1/2, MLH1, MSH2, ATM, ATR, MDC1, PARP1, FANCF) were altered in 90.1 % of cases, and 17 PI3K pathway genes were altered in 88.9 % of cases.Our ER+ve patients presented a diverse variety of PIK3CA mutations (E545K,  E545A, E545G, E542K, E453K, E762K, E365K, N345K, C420R, E81K, Q546R, C420R, E726K, E81K, E970K, H1047R, H1047L P104L, P539R, G106R,G1049R, R93Q,N345T, V105_E109&gt;E, L113del, K111del) as compared to a less diverse type of PIK3CA mutations (Amplification, E542K, H1047R) in our TNBC patients. In our TNBC patients, the predominant type of mutation in PI3K pathway genes was found in PTEN consisting of Y68C, Y180*, loss, loss exons 1-5, and deletion exon1. The other most common mutation found in TNBC patients was in TP53 (&gt;80%) and somatic BRCA1/2 (˜15%) genes. The interaction between the two pathways was evaluated using the mostly altered oncogenes and tumor suppressor genes (PTEN, AKT1/2, TSC1/2, mTOR, RICTOR, RHEB, BRCA1/2, ATM, ATR, FANCF) applying STRING10 to test the association at the highest 0.900 confidence views. Finally, we experimentally validated the contextual synergy of 2 pathways by demonstrating that a node-specific inhibition of the PI3K-mTOR pathway by GDC-0980 in the presence of carboplatin resulted in (1) an enhanced impairment of DSB repair and (2) a subsequent sensitization to PARPi (i). This effect occurred simultaneously with the inhibition of classic PI3K-mTOR survival signal(s) which induced a robust antiproliferative/proapoptotic effect even in BRCA-competent TNBC cells. The absence of PTEN, on the other hand, sensitized TNBC cells to PARPi in the presence of carboplatin, an effect more pronounced in BRCA-loss. Conclusion: Our data showed that the PI3K pathway cooperates with the DDR pathway in the breast oncogenesis especially basal-like and TNBC.

Citation Format: Dey N, Williams C, Krie A, Klein J, Williams K, Carlson JH, De PK, Leyland-Jones B. A tale of two pathways: Mutations in PI3K pathway in TNBC patients matter for the oncogenic cooperation with DNA damage repair pathway [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD4-15.