Cancer treatment targeted to tumor adaptive responses to protein synthesis stress
In cancers such as prostate cancer, the combination of PTEN loss and activation of Myc activates an adaptive stress response that enables tumor cells to escape the stress of massively upregulated protein synthesis. This pro-survival response is mediated by the PERK-phosphorylated eIF2α axis of the UPR adaptive response. Agents that disrupt PERK-eIF2α pathways disrupt the adaptive response and lead to cancer cell death from uncontrolled growth. For example, ISRIB and derivatives may be employed as therapeutic agents to disrupt PERK-mediated adaptive mechanisms. Additionally PTEN loss and activation of Myc provides a diagnostic marker that enables better prognosis and the selection of amenable treatments.
1. A method of treating cancer in a subject,
comprising the steps of:
obtaining a sample comprising cancerous cells from the subject;
assessing PTEN loss in the cancerous cells;
assessing Myc activation in the cancerous cells; and
wherein, if both PTEN loss and Myc activation in the cancerous cells is observed, administering to the subject a pharmaceutically active amount of an agent which inhibits the PERK-mediated integrated stress response, wherein the cancerous cells of the subject comprise prostate cancer cells.
2. The method of claim 1 , wherein
the agent which inhibits the PERK-mediated integrated stress response comprises an agent which renders cells insensitive to the effects of eIF2α phosphorylation.
3. The method of claim 2 , wherein
the agent which inhibits the PERK-mediated integrated stress response comprises ISRIB.
4. The method of claim 1 , wherein
the agent which inhibits the PERK-mediated integrated stress response comprises an inhibitor of PERK expression, translation, or kinase activity.
5. The method of claim 4 , wherein
the inhibitor of PERK expression, translation, or kinase activity comprises GSK2606414 or GSK2656157.
6. The method of claim 1 , wherein
the agent which inhibits the PERK-mediated integrated stress response is an ATF4 inhibitor.