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Importance of PKN2 Signaling in the Development of Drug Resistance in Patients with CCA and FGFR2 Fusion

2020 Year in Review: Cholangiocarcinoma — December 19, 2020

Preclinical evidence presented at the AACR meeting implicates PKN2 signaling in resistance mechanisms in patients with FGFR2 fusion–positive intrahepatic CCA.

Chemotherapy, radiation, and surgery are all conventional antitumor therapies. After the identification of molecular aberrations as drivers for carcinogenesis, the introduction of therapies targeting specific tumor-promoting pathways has revolutionized the development of cancer therapeutics.

Significant progress has been made in cancer therapy, but oncologists often face the challenge of drug resistance, as many patients with cancer have resistance from the onset of treatment or after initial responses or several treatment cycles. This resistance results in acquired drug resistance and relapses, leading to increased mortality.

Resistance mechanisms in patients with FGFR2 fusion–positive intrahepatic CCA were investigated by Yeonjoo Hwang, BS, Staff Research Associate, University of California, San Francisco, and colleagues. Results were presented at this year’s annual meeting of the American Association for Cancer Research.

FGFR inhibition is associated with the rapid emergence of drug resistance. The mechanisms of FGFR resistance are diverse and include mutations that block drugs from binding to receptor sites. But it is becoming increasingly clear that individual tumors may achieve drug resistance via multiple routes simultaneously based on previous work.

Ms Hwang and colleagues used a phosphoproteomic (ie, a branch of proteomics that identifies, catalogs, and characterizes proteins that contain a phosphate group) analysis of the FGFR2-driven signaling response of a patient-derived FGFR2 fusion–positive intrahepatic CCA with cell line to the FGFR inhibitor TAS-120 (currently in phase 2 clinical trials, in development by Taiho Oncology). They identified a protein kinase, the PKN2, which significantly regulates the sensitivity to inhibition of FGFR fusion and FGFR signaling. PKN2 modulates signaling feedback through the AKT pathway after inhibition of FGFR fusion.

AKT is a key effector in PKN2-mediated FGFR resistance, and its pathway is important. When activated, AKT upregulates the NF-кB pathway, potentially leading to cell survival despite the inhibition of FGFR.

To validate that AKT is the pathway through which the PKN2 is regulating the NF-кB pathway, Ms Hwang and colleagues plan to continue this line of research, which will therefore contribute to drug resistance in patients with CCA and FGFR2 fusion.

Source: Hwang Y, et al. Cancer Res. 2020;80(16_suppl). Abstract 6572.

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