Long-term ERK inhibition induces KRAS-mutant PDAC cell senescence mediated by MYC degradation.
Major finding: Long-term ERK inhibition induces KRAS-mutant PDAC cell senescence mediated by MYC degradation.
Clinical relevance: De novo resistance to ERK inhibition was associated with elevated PI3K–AKT–mTOR signaling.
Impact: ERK inhibitors may be more effective than RAF or MEK inhibitors in treating KRAS-mutant tumors.
Most pancreatic ductal adenocarcinomas (PDAC) harbor activating KRAS mutations, which lead to the activation of RAF–MEK–ERK signaling. However, resistance to RAF or MEK inhibitors can occur through ERK reactivation in KRAS-mutant cells, suggesting that ERK may be a better target in KRAS-mutant tumors. Hayes and colleagues showed that approximately half of PDAC cell lines were sensitive to the ERK inhibitor SCH772984, including cell lines that were resistant to MEK inhibition. Short-term SCH772984 treatment reduced phosphorylation of ERK (pERK) and RSK (an ERK target), and reduced tumor cell growth through induction of apoptosis and inhibition of cell-cycle progression. SCH772984 also induced pAKT in PDAC cells sensitive to SCH772984, resulting in increased pAKT. Combining AKT inhibition (with the PI3K inhibitor AZD8186) with ERK inhibition resulted in further growth inhibition in SCH772984-sensitive cells, suggesting that combined ERK and PI3K inhibition may be effective in treating PDAC. Unexpectedly, outgrowth of resistant cells did not occur after long-term treatment of sensitive cells with SCH772984. ERK inhibition promoted a senescence-like phenotype associated with p16 upregulation and decreased RB phosphorylation that was dependent on degradation of MYC. In a PDAC orthotopic mouse model, SCH772984 treatment decreased pERK expression, reduced MYC levels, and suppressed tumor growth. De novo resistance to ERK inhibition was associated with elevated PI3K–AKT–mTOR signaling, but combined inhibition of PI3K did not overcome resistance, indicating more complex mechanisms driving de novo resistance. Combined treatment with SCH772984 and the CDK inhibitor dinaciclib improved tumor suppression, and the combined inhibition of ERK and PI3K also slowed tumor growth. Together, these data suggest that ERK inhibitors may be effective in treating patients with PDAC and potentially other KRAS-mutant cancers, and elucidate a mechanism by which short- and long-term ERK inhibition has differential effects.
Hayes TK, Neel NF, Hu C, Gautam P, Chenard M, Long B, et al. Long-term ERK inhibition in KRAS-mutant pancreatic cancer is associated with MYC degradation and senescence-like growth suppression. Cancer Cell 2016;29:75–89.
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