Abstract IA22: Rationale and current status of development of PI3K/TOR pathway inhibitors
Authors: Arteaga Carlos L. 
Published: May 2015

The PI3K/AKT pathway is the most frequently mutated pathway in breast cancer, with mutation and/or amplification of the genes encoding the PI3K catalytic subunits p110α (PIK3CA) and p110β (PIK3CB), the PI3K regulatory subunit p85α (PIK3R1), receptor tyrosine kinases (RTKs) such as HER2 (ERBB2) and FGFR1, the PI3K activator K-Ras, the PI3K effectors AKT1, AKT2, and PDK1, and loss of the lipid phosphatases PTEN and INPP4B. The three genes PIK3CA, PIK3CB, and PIK3CD encode the homologous p110α , p110β, and p110δ isozymes, respectively. Expression of p110δ; is largely restricted to immune and hematopoietic cells, whereas p110α and p110β are ubiquitously expressed. The p110α isozyme is essential for signaling and growth of tumors driven by PIK3CA mutations, RTKs, and/or mutant Ras, whereas p110β lies downstream of GPCRs and has been shown to mediate tumorigenesis in PTEN-deficient cells. PIK3CA mutations are the most common genetic alterations of this pathway, where ≥80% occur within the helical (E542K and E545K) and kinase (H1047R) domains of p110α. Such mutations confer increased catalytic activity through different mechanisms, but both induce characteristics of cellular transformation including growth factor- and anchorage-independent growth, and resistance to anoikis.

Several drugs targeting multiple levels of the PI3K network (i.e., PI3K, AKT, mTOR) have been developed (Table 1). A number of ATP-mimetics that bind competitively and reversibly to the ATP-binding pocket of p110 are in early clinical development. These include the pan-PI3K inhibitors BKM120, XL-147, PX-866, PKI-587, and GDC-0941, the p110α-specific inhibitors BYL719, GDC-0032, and INK-1117, the p110δ-specific inhibitor CAL-101, and the dual PI3K/mTOR inhibitors BEZ235, BGT226, PF-4691502, GDC-0980, and XL-765. The pan-PI3K and p110α-specific inhibitors are equally potent against oncogenic p110α mutants. The rationale for the development of isozyme-specific antagonists is to allow higher doses of anti-p110α and anti-p110β drugs to be delivered without incurring side-effects caused by pan-PI3K inhibitors. Recently completed phase I trials with BKM120, BEZ235, and XL-147 showed that treatment partially inhibited PI3K as measured by levels of P-S6 and P-AKT in patients' skin or tumors, and 2-deoxy-2-[18F]fluoro-D-glucose (FDG) uptake measured by PET. Main toxicities were rash, hyperglycemia, diarrhea, fatigue and, mood alterations. Few clinical responses were observed in patients with and without detectable PI3K pathway mutations, although screening for genetic lesions in this pathway was not comprehensive.

Both allosteric and ATP-competitive pan-inhibitors of the three isoforms of AKT are also being developed. AZD5363, GDC-0068, GSK2141795, and GSK690693 are ATP-competitive compounds which have shown antitumor activity in preclinical models and recently entered phase I trials. Allosteric inhibitors such as MK-2206 bind to the AKT PH domain and/or hinge region to promote an inactive conformation of the AKT protein that is unable to bind to the plasma membrane. MK-2206 inhibits AKT signaling in vivo, and suppresses growth of breast cancer xenografts harboring PIK3CA mutations or ERBB2 amplification. Phase I data showed that treatment with MK-2206 decreases levels of P-AKT, P-PRAS40, and P-GSK3β in tumor cells, peripheral blood mononuclear cells, and hair follicles. Another approach to block this pathway has been the development of ATP-competitive inhibitors of the mTOR kinase, which block both mTORC1 and mTORC2. Several dual TORC1/2 inhibitors have been identified, including INK128 (Intellikine), CC223 (Celgene), AZD2014 (AstraZeneca), and Palomid 529 (Paloma Pharmaceuticals). Dual PI3K/mTOR inhibitors have also been developed in the hope of overcoming the loss of feedback inhibition or PI3K activation observed with rapalogs. The mTORC1 pathway is one of the prominent negative feedback regulators of the PI3K pathway; inhibition of mTORC1 can release this feedback inhibition and activate the PI3K pathway19. BEZ235, a dual PI3K/mTOR inhibitor, showed higher anti-proliferative activity than rapamycin in a preclinical study trastuzumab-resistant and –sensitive human breast cancer cell lines. In breast cancer, dual PI3K/mTOR inhibitors are being combined with everolimus, endocrine therapies (exemestane and letrozole), chemotherapy (paclitaxel), and anti-HER2 therapy (trastuzumab).

Citation Format: Carlos L. Arteaga. Rationale and current status of development of PI3K/TOR pathway inhibitors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr IA22.