AKT inhibition: a bad AKT inhibitor in liver injury and tumor development?

Cells respond to growth signals by activating internal programs that coordinate growth, division and death. One of these, the PI3K/AKT pathway, is frequently activated in human cancer (1). The serine/threonine kinase AKT is a key actor that regulates development, metabolism and the immune response (2,3).

Two decades of intense scrutiny have given us several AKT inhibitors to test as cancer therapeutics. Some have entered clinical trial, so it is important to define mechanisms underlying their therapeutic and toxic effects. Investigators frequently model the effects of an inhibitor with a germ-line knockout (KO) of the inhibitor’s gene target in mice. However, we know that gene KO during development may mask a role in the adult. To study how adults respond to Akt loss, Wang et al. conditionally knocked out Akt in adult mice, both systemically and in the liver (4). This approach unmasked unexpected potential toxicities of AKT inhibitors.

The three members of the Akt family are Akt1, Akt2 and Akt3. Their genetic sequences are quite similar, but we know they have both overlapping and distinct functions and substrates (5). Wang and colleagues find Akt1 and Akt3 ablation does not kill adult mice. However, concomitant, systemic deletion of Akt1 and Akt2 cause liver inflammation, hypoglycemia and death. The authors speculate intestinal damage inhibits nutrient absorption, shifting the animal’s primary energy supply to fatty acid oxidation. Once the animal exhausts fat stores, hypoglycemia and death rapidly ensue. Effects of a moderately high dose of the pan AKT inhibitor MK2206 in mice are similar but reversible. Thus, this work illuminates a possible toxicity for pan AKT inhibitors.

The surprise in this study is that liver Akt1 ablation in adult Akt2^−/− mice causes hepatocellular carcinoma (HCC). This was unexpected since Akt overexpression and pathway activation are implicated in HCC development (6-8). The authors find that Akt1 and Akt2 ablation increases liver injury and inflammation. Markers of proliferation are expressed within the hepatic tumors, while adjacent normal tissue expresses apoptotic markers. Thus Akt1 and Akt2 deletion in livers of adult mice induces hepatocyte cell death and liver inflammation that progresses to HCC. Akt can suppress apoptosis by inhibiting FoxO transcription factors. This cascade is largely dependent on FoxO1 since deleting hepatic FoxO1 along with Akt1 and Akt2 protects mice from liver damage, inflammation and HCC.

The authors also investigate Akt1 and Akt2 involvement in liver tumor development using a chemically induced model of HCC. Individual knockout of Akt1 or Akt2 does not change the frequency of tumor induction. Rather Akt2 ablation increases HCC pulmonary metastasis. They speculate that high insulin levels in Akt2 KO mice increase Akt1 activation and metastasis. So here we see an unexpected potential negative side effect of inhibiting Akt2—accelerated HCC progression.

Previous work indicates obesity significantly increases the risk of HCC (9,10) through stimulation of liver damage and inflammation (11). These patients also have hepatic insulin resistance and decreased AKT signaling. This study implicates reduced hepatic AKT signaling in the genesis of obesity-induced HCC. One concern is that pan-AKT inhibitors that further suppress AKT signaling will exacerbate the increase in HCC seen in obese patients.

AKT inhibitors are slowly advancing through clinical trials. These results raise the possibility that pan AKT inhibitors cause liver injury and inflammation and possibly HCC. The work suggests that trials carefully monitor patients for liver damage and pro-tumorigenic side effects. We need further studies to determine whether there is a window where benefits of AKT anti-tumor activity outweigh risk of these serious toxicities. Furthermore, we do not know whether drugs targeting other sites in the PI3K/AKT pathway will have similar side effects. Currently tested AKT inhibitors target all isoforms and include the ATP competitive inhibitor GSK690693 and allosteric inhibitor MK2206. Second generation allosteric inhibitors with isozyme specificity are under development and may reduce toxicities associated with pan AKT inhibitors.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Bo Zhai (Department of Hepatobiliary Surgery, The Fourth Hospital of Harbin Medical University, Harbin, China).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2016.11.44). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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