Details

Autor(en) / Beteiligte

• Wu, Qibiao
• Zhen, Yuanli
• Shi, Lei
• Vu, Phuong
• Greninger, Patricia
• Adil, Ramzi
• Merritt, Joshua
• Egan, Regina
• Wu, Meng-Ju
• Yin, Xunqin
• Ferrone, Cristina R
• Deshpande, Vikram
• Baiev, Islam
• Pinto, Christopher J
• McLoughlin, Daniel E
• Walmsley, Charlotte S
• Stone, James R
• Gordan, John D
• Zhu, Andrew X
• Juric, Dejan
• Goyal, Lipika
• Benes, Cyril H
• Bardeesy, Nabeel

Titel

EGFR Inhibition Potentiates FGFR Inhibitor Therapy and Overcomes Resistance in FGFR2 Fusion-Positive Cholangiocarcinoma

Ist Teil von

• Cancer discovery, 2022-05, Vol.12 (5), p.1378-1395

Ort / Verlag

United States

Erscheinungsjahr

2022

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• FGFR inhibitors are approved for the treatment of advanced cholangiocarcinoma harboring FGFR2 fusions. However, the response rate is moderate, and resistance emerges rapidly due to acquired secondary FGFR2 mutations or due to other less-defined mechanisms. Here, we conducted high-throughput combination drug screens, biochemical analysis, and therapeutic studies using patient-derived models of FGFR2 fusion-positive cholangiocarcinoma to gain insight into these clinical profiles and uncover improved treatment strategies. We found that feedback activation of EGFR signaling limits FGFR inhibitor efficacy, restricting cell death induction in sensitive models and causing resistance in insensitive models lacking secondary FGFR2 mutations. Inhibition of wild-type EGFR potentiated responses to FGFR inhibitors in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo. Our findings reveal EGFR-dependent adaptive signaling as an important mechanism limiting FGFR inhibitor efficacy and driving resistance and support clinical testing of FGFR/EGFR inhibitor therapy for FGFR2 fusion-positive cholangiocarcinoma. We demonstrate that feedback activation of EGFR signaling limits the effectiveness of FGFR inhibitor therapy and drives adaptive resistance in patient-derived models of FGFR2 fusion-positive cholangiocarcinoma. These studies support the potential of combination treatment with FGFR and EGFR inhibitors as an improved treatment for patients with FGFR2-driven cholangiocarcinoma. This article is highlighted in the In This Issue feature, p. 1171.