Tumors with AKT1E17K Mutations Are Rational Targets for Single Agent or Combination Therapy with AKT Inhibitors

Abstract

AKT1E17K mutations occur at low frequency in a variety of solid tumors, including those of the breast and urinary bladder. Although this mutation has been shown to transform rodent cells in culture, it was found to be less oncogenic than PIK3CA mutations in breast epithelial cells. Moreover, the therapeutic potential of AKT inhibitors in human tumors with an endogenous AKT1 E17K mutation is not known. Expression of exogenous copies of AKT1 E17K in MCF10A breast epithelial cells increased phosphorylation of AKT and its substrates, induced colony formation in soft agar, and formation of lesions in the mammary fat pad of immunodeficient mice. These effects were inhibited by the allosteric and catalytic AKT inhibitors MK-2206 and AZD5363, respectively. Both AKT inhibitors caused highly significant growth inhibition of breast cancer explant models with AKT1 E17K mutation. Furthermore, in a phase I clinical study, the catalytic Akt inhibitor AZD5363 induced partial responses in patients with breast and ovarian cancer with tumors containing AKT1 E17K mutations. In MGH-U3 bladder cancer xenografts, which contain both AKT1 E17K and FGFR3 Y373C mutations, AZD5363 monotherapy did not significantly reduce tumor growth, but tumor regression was observed in combination with the FGFR inhibitor AZD4547. The data show that tumors with AKT1 E17K mutations are rational therapeutic targets for AKT inhibitors, although combinations with other targeted agents may be required where activating oncogenic mutations of other proteins are present in the same tumor.

3D clusters of somatic mutations in cancer reveal numerous rare mutations as functional targets

“…For example, a 3D cluster in AKT1 (R15, E17, W22, and D323) did not score as statistically significant ( p  = 0.11) as a 3D cluster. There is no issue with the fact that the cluster contains the most frequent single-residue hotspot mutation E17K, which has been evaluated as an indicator of response to AKT-targeted inhibitors in clinical trials [44]. But D323 is not identified as a candidate by our method on the current dataset, while experimental in vitro studies indicate that AKT1 D323 mutations lead to constitutive activation of AKT [45].…”

Combination treatment of prostate cancer with FGF receptor and AKT kinase inhibitors

“…AZD5363 is an AKT kinase inhibitor that has been shown to have activity against many cancer types in vitro and in vivo [21, 22, 24]. Multiple publications have shown the efficacy of AZD5363 against a broad array of PCa cell lines in vitro and in vivo [22, 25–28].…”

“…Davies et al [24] reported that a bladder cancer cell line with activating mutations of both AKT and FGFR3 responded poorly to AZD5363 compared to breast cancer models with the same AKT mutation but responded significantly better to combination therapy with AZD4547 and AZD5363 compared to monotherapy with either agent. This result supports the concept that FGFR and AKT kinase activation can mediate cross resistance between these two pathways.…”

Molecular predictive markers in tumors of the gastrointestinal tract

“…The only mutation observed is the activating mutation E17K , which is also observed in other types of cancer[64]. AKT1 is a critical component of the PI3K/AKT/mTOR pathway, thus it has become an attractive target for therapeutic intervention[49,65]. AKT1 E17K mutations have also been associated with primary resistance to cetuximab[66].…”