Combination of PI3K/mTOR and EGFR inhibitors suppresses KRAS-mutant colorectal cancer


Some selective inhibitors, particularly those against kinases, have shown promising initial efficiency in blocking oncogenic driver signaling. However, difficulties still exist, such as limited duration of response, rapidly emerged drug resistance, etc. Due to the limited clinical efficiency of single agents in inhibiting KRAS-mutant colorectal cancer (CRC), Belmont et al. demonstrated a new therapeutic strategy in combination of phospharidylinositol 3-kinase/mechanistic target of rapamycin (PI3K/mTOR) and epidermal growth factor receptor (EGFR) inhibitors. The article was published on Science Signaling, recently.


KRAS gene, which encodes he guanosine triphosphatase, is frequently mutant in human cancer. Unfortunately, the effective targeted strategies of inhibiting mutant KRAS activity are lacking. Researchers established a mouse cell lineage that resistant to inhibitor PF-04691502, which targets to PI3K and mTOR, two KRAS signaling mediators. What they found was, EGFR inhibitors restored the sensitivity to PF-04691502. Also, PF-04691502 can increase the expression, phosphorylation levels of EGFR, ERBB2, and ERBB3 by activating forkhead box O 3a (FOXO3a), usually inhibited by PI3K/AKT pathway. For the in vivo experiment, combination treatment of PF-04691502 with a pan-ERBB inhibitor, dacomitinib, inhibited tumor development in drug-resistant mice. The results indicates the combination of PI3K/mTOR and EGFR inhibitors may become a novel therapy in patients with KRAS-mutant CRC.


Sci Signal. 2014 Nov 11;7(351):ra107

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S2743 PF-04691502 PF-04691502 (PF4691502) is an ATP-competitive PI3K(α/β/δ/γ)/mTOR dual inhibitor with Ki of 1.8 nM/2.1 nM/1.6 nM/1.9 nM and 16 nM in cell-free assays, little activity against either Vps34, AKT, PDK1, p70S6K, MEK, ERK, p38, or JNK. PF-04691502 induces apoptosis. Phase 2. (36) (4)
S2727 Dacomitinib (PF-00299804) Dacomitinib (PF299804, PF299) is a potent, irreversible pan-ErbB inhibitor, mostly to EGFR with IC50 of 6 nM in a cell-free assay. Dacomitinib inhibits ERBB2 and ERBB4 with IC50 of 45.7 nM and 73.7 nM, respectively. Dacomitinib is effective against NSCLCs with EGFR or ERBB2 mutations (resistant to gefitinib) as well as those harboring the EGFR T790M mutation. Dacomitinib inhibits cell growth and induces apoptosis. Phase 2. (63) (4)

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