Editors' ChoiceCancer

Dual oncogene excision is greater than the sum of its parts

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Science Translational Medicine  08 May 2019:
Vol. 11, Issue 491, eaax4876
DOI: 10.1126/scitranslmed.aax4876

Abstract

Ablation of EGFR and c-RAF in combination is effective against aggressive pancreatic tumors.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest and least treatable tumors, in part because it is driven by undruggable mutated proteins, such as KRAS and TP53. Consequently, there is a clear, unmet need to find new treatments for this type of cancer and to improve the survival rates.

Blasco and colleagues used genetically engineered mouse PDAC models driven by mutant Kras (Kirsten rat sarcoma viral oncogene homolog gene encoding for the K-RASG12V protein) and loss of Trp53 (transformation-related protein 53 gene), which closely reproduce human tumors, to identify druggable targets to treat this deadly disease. Using models with conditional floxed alleles, they observed that concomitant elimination of Efgr (epidermal growth factor receptor gene) and Raf1 (proto-oncogene encoding for the c-RAF kinase) induced a complete regression in these PDAC tumors, whereas targeting Cdk4 (cyclin-dependent kinase 4 gene) was ineffective. Only a small percentage of mice did not respond to Efgr and Raf1 elimination, and transcriptional analyses revealed that their tumors displayed a “squamous” subtype profile with distinct enriched pathways, similar to the signatures of human PDAC with poor prognosis. Nonetheless, this dual targeting strategy was successful for most PDAC mouse models. Ablation of EGFR expression had manageable toxic effects, similar to those observed in human patients treated in the clinic with EGFR inhibitors. Similarly, c-RAF removal had no major toxicities, in contrast to pan-RAF or MEK inhibition, which have profound secondary effects in patients. Therefore, the authors suggest that dual inhibition of EGFR and c-RAF, without completely inhibiting the mitogen-activated protein kinase (MAPK) pathway, could be a promising therapy for PDAC treatment. In fact, similar results were observed in human patient–derived pancreatic tumor xenografts carrying KRAS and TP53 (human tumor protein p53 gene) mutations when knocking down EGFR and c-RAF or when pharmacologically inhibiting the first and knocking down the latter.

The biggest challenge in translating these results into the clinic, as the authors point out, will be the development of specific c-RAF inhibitors capable of effectively blocking this protein, including its kinase-independent activities. In conclusion, this paper elegantly demonstrates in mouse models that a dual inhibition of EGFR and c-RAF may be effective for treating mutant KRAS/TP53-driven PDAC tumors with few secondary effects.

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