AZD2014, an Inhibitor of mTORC1 and mTORC2, Is Highly Effective in ER+ Breast Cancer When Administered Using Intermittent or Continuous Schedules

Abstract

mTOR is an atypical serine threonine kinase involved in regulating major cellular functions, such as nutrients sensing, growth, and proliferation. mTOR is part of the multiprotein complexes mTORC1 and mTORC2, which have been shown to play critical yet functionally distinct roles in the regulation of cellular processes. Current clinical mTOR inhibitors only inhibit the mTORC1 complex and are derivatives of the macrolide rapamycin (rapalogs). Encouraging effects have been observed with rapalogs in estrogen receptor-positive (ER þ ) breast cancer patients in combination with endocrine therapy, such as aromatase inhibitors. AZD2014 is a small-molecule ATP competitive inhibitor of mTOR that inhibits both mTORC1 and mTORC2 complexes and has a greater inhibitory function against mTORC1 than the clinically approved rapalogs. Here, we demonstrate that AZD2014 has broad antiproliferative effects across multiple cell lines, including ER þ breast models with acquired resistance to hormonal therapy and cell lines with acquired resistance to rapalogs. In vivo, AZD2014 induces dose-dependent tumor growth inhibition in several xenograft and primary explant models. The antitumor activity of AZD2014 is associated with modulation of both mTORC1 and mTORC2 substrates, consistent with its mechanism of action. In combination with fulvestrant, AZD2014 induces tumor regressions when dosed continuously or using intermittent dosing schedules. The ability to dose AZD2014 intermittently, together with its ability to block signaling from both mTORC1 and mTORC2 complexes, makes this compound an ideal candidate for combining with endocrine therapies in the clinic. AZD2014 is currently in phase II clinical trials.

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

“…S1A). 6 This contrasted treatment with rapamycin, which promoted an extremely potent inhibitory effect on pS6 (Ser240/244) at sub-pM concentrations (Fig. S1B).…”

“…Vistusertib (AZD2014) is a potent, orally available, mTOR kinase inhibitor, with a reported IC 50 in sensitive tumour cell lines of between 100-200 nM, 6 and is under investigation as a tumour targeted agent against both solid and hematological malignancies. To investigate whether primary immune cells were sensitive to vistusertib treatment, we first asked whether vistusertib inhibited downstream mTOR pathway targets in primary CD8 + T-cells.…”

“…19,20 We confirmed this prediction, observing that CT-26 tumours were insensitive to vistusertib when delivered with a regimen that promotes anti-tumour efficacy in sensitive tumour cell lines. 6 . Interestingly, vistusertib potentiated anti-tumour efficacy when co-administered as a combination therapy with αCTLA-4 immune-checkpoint blockade (Fig.…”

“…3-5 Therapeutic mTOR inhibition has been well studied as a tumour targeting agent in the context of many tumour types, including ER + breast cancer in combination with endocrine therapy. 6 mTOR kinase functions in the context of multiprotein complexes termed mTORC1 and mTORC2, which under physiological conditions can be engaged by a variety metabolic, stress and immunological signals in immune cell populations. Inhibitors of mTOR signalling have been long believed to be profoundly immunosuppressive, and blockade of mTOR signalling with the allosteric mTORC1 inhibitor rapamycin inhibits effector T-cell expansion following mitogen treatment.…”

Molecular Docking and Pharmacokinetic of Highly Specific Novel Pan-Mtor Inhibitors against Solid Tumors

“…AZD2014 or 3-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-N-methylbenzamide, analogue of AZD8055 is a novel and highly specific mTOR kinase domain inhibitor present in Phase 2 of clinical trials [29] (Figure 2a). All nine binding modes are shown in (Figure 3).…”