Data from MTORC1/2 Inhibition as a Therapeutic Strategy for <i>PIK3CA</i> Mutant Cancers

Abstract

&lt;div&gt;Abstract&lt;p&gt;&lt;i&gt;PIK3CA&lt;/i&gt; mutations are common in clinical molecular profiling, yet an effective means to target these cancers has yet to be developed. MTORC1 inhibitors are often used off-label for patients with &lt;i&gt;PIK3CA&lt;/i&gt; mutant cancers with only limited data to support this approach. Here we describe a cohort of patients treated with cancers possessing mutations activating the PI3K signaling cascade with minimal benefit to treatment with the MTORC1 inhibitor everolimus. Previously, we demonstrated that dual PI3K/mTOR inhibition could decrease proliferation, induce differentiation, and result in a treatment response in &lt;i&gt;APC&lt;/i&gt; and &lt;i&gt;PIK3CA&lt;/i&gt; mutant colorectal cancer. However, reactivation of AKT was identified, indicating that the majority of the benefit may be secondary to MTORC1/2 inhibition. TAK-228, an MTORC1/2 inhibitor, was compared with dual PI3K/mTOR inhibition using BEZ235 in murine colorectal cancer spheroids. A reduction in spheroid size was observed with TAK-228 and BEZ235 (−13% and −14%, respectively) compared with an increase of &gt;200% in control (&lt;i&gt;P&lt;/i&gt; &lt; 0.001). These spheroids were resistant to MTORC1 inhibition. In transgenic mice possessing &lt;i&gt;Pik3ca&lt;/i&gt; and &lt;i&gt;Apc&lt;/i&gt; mutations, BEZ235 and TAK-228 resulted in a median reduction in colon tumor size of 19% and 20%, respectively, with control tumors having a median increase of 18% (&lt;i&gt;P&lt;/i&gt; = 0.02 and 0.004, respectively). This response correlated with a decrease in the phosphorylation of 4EBP1 and RPS6. MTORC1/2 inhibition is sufficient to overcome resistance to everolimus and induce a treatment response in &lt;i&gt;PIK3CA&lt;/i&gt; mutant colorectal cancers and deserves investigation in clinical trials and in future combination regimens.&lt;/p&gt;&lt;/div&gt;