Abstract 3882: tumor adaptations to PI3K inhibition increases and its reversibility decreases as a function of time in drug
Authors: Mukherjee Radha , Vanaja Kiran Gireesan , Sharma Malvika , Ruan Yangjingyi Ruan , Solomon Hilla , deStanchina Elisa , Chandarlapaty Sarat , Rosen Neal 
Published: April 2023

Abstract
The PI3K pathway is a key regulator of metabolism, cell proliferation and migration and some of its components (e.g. PIK3CA, HER2 and PTEN) are frequently altered in cancer by genetic events that deregulate its output. However, inhibitors of components of the pathway have only modest antitumor effects and, in some instances, have resulted in “tumor flares” in patients upon cessation of therapy. Low efficacy has been attributed to toxicity and to adaptive resistance due to relief of feedback. Inhibition of the PI3K pathway has been associated with increased receptor expression and decreased expression of the PTEN phosphatase, a major negative regulator of the pathway. Now we show that changes in expressions of RTKs, PTEN, anti-apoptosis proteins like Mcl1, and transcription factors known to drive oncogenic and survival programs in tumors like c-Myc, c-Jun, FOXOs are induced upon continuous long-term PI3K inhibition (2 weeks and longer). These changes increase as a function of duration of inhibition and become less reversible with time in drug. Unbiased clustering of RNA seq data of cells treated with PI3K inhibitors revealed clusters of gene expression changes based upon short or long-term inhibition. Correspondingly the mRNA of the RTKs and transcription factors change with similar kinetics as that of the proteins and become less reversible with duration of inhibition. Moreover, the persister cells treated with PI3K inhibitors for 2 weeks or longer grow faster than the treatment naive cells upon drug removal both in vitro and in vivo and the degree of reversibility of the increased proliferation rate is inversely proportional to the duration of inhibition. Persister cells treated with PI3K inhibitors for more than two weeks have higher levels of expression of a oncogenic transcription factors, RTKs, Mcl1, and of pAKT after one week of drug wash-out and are less sensitive to re-inhibition of PI3K. However, combined and staggered inhibition of PI3K with Mcl1/Bcl2 inhibitors lead to greater reduction of cell survival and increased cell death selectively in the models that upregulate Mcl1 in response to PI3K inhibitors. The data suggests that induction of adaptive resistance is in part responsible for the continued persistence of tumor masses after the initial response to targeted therapy but also selectively sensitizes them towards Mcl1/Bcl2 inhibitors due to the upregulation of an anti-apoptotic program. Therefore, pulsatile targeted inhibition of PI3K in combination with anti-apoptotic BH3 domain protein inhibitors in a subset of breast cancer patients may provide a wide therapeutic window and can circumvent chronic adaptation induced resistance and drive potent cell death thereby improving therapeutic outcomes.
Citation Format: Radha Mukherjee, Kiran Gireesan Vanaja, Malvika Sharma, Yangjingyi Ruan Ruan, Hilla Solomon, Elisa deStanchina, Sarat Chandarlapaty, Neal Rosen. tumor adaptations to PI3K inhibition increases and its reversibility decreases as a function of time in drug. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3882.