Combined EGFR and CRAF Inhibition Induces Complete PDAC Regression in Mice

Current therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC) suffer from low antitumor efficacy and high toxicity. Although mutations in KRAS are the most common driving event for PDAC, secondary mutations in genes such as TP53 contribute to tumor progression. Blasco, Navas, and colleagues show in Kras/Trp53-mutant (KPC) PDAC that combined inhibition of EGFR and CRAF leads to complete tumor regression. In a modified murine KPC model of PDAC where mutant Kras is expressed only in the acinar cell compartment, individual ablation of Egfr or Raf1 (encoding CRAF) led to a modest increase or no change in median survival, respectively. By contrast, combined ablation of Egfr and Raf1 during tumor initiation completely prevented PDAC development to 2 years of age, with no indication of PanIN lesions or metaplasias. Targeted deletion of Egfr and Raf1 had no effect on MAPK and PI3K signaling, thus preventing major toxicities. Indeed, only minor alterations to skin cells, such as hyperplasia, inflammation, hair loss, ulceration, and scabbing, were observed due to lack of EGFR expression. In advanced PDAC, ablation of Egfr and Raf1 resulted in apoptosis of tumor cells, regression of tumor volume, extended survival, and reversion to normal tissue architecture within the pancreas. Transcriptional profiling of tumor-derived cell lines revealed significant changes in metabolic signaling pathways, and mice nonresponsive to Egfr/Raf1 ablation exhibited increased phosphorylation of STAT3 and multiple pro-proliferative gene signatures, suggesting these alternative pathways promote tumor growth independently of EGFR/CRAF signaling. In patient-derived PDAC xenografts (PDX), combined pharmacologic inhibition of EGFR and knockdown of CRAF inhibited proliferation in cells derived from 9 out of 10 tumors. Collectively, these results demonstrate that inhibition of EGFR and CRAF signaling exerts significant antitumor effects with low toxicity and may be a viable therapeutic strategy for patients with PDAC.

Blasco MT, Navas C, Martín-Serrano G, Graña-Castro O, Lechuga CG, Martín-Díaz L, et al. Complete regression of advanced pancreatic ductal adenocarcinomas upon combined inhibition of EGFR and C-RAF. Cancer Cell 2019;35:573–87.e6.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.