Cholangiocarcinoma News

PKN2 Signaling Plays an Important Role in the Development of Drug Resistance in Patients with Cholangiocarcinoma and FGFR2 Fusion

August 2020, Vol 1, No 1

Conventional antitumor therapies include chemotherapy, radiation, and surgery. After the identification of molecular aberrations as drivers for carcinogenesis, the introduction of therapies that target specific tumor-promoting pathways has revolutionized the development of cancer therapeutics.

Despite the significant progress in cancer therapy, oncologists often face the challenge of drug resistance, because many patients with cancer have resistance from the very beginning of treatment or after initial responses or several treatment cycles, resulting in acquired drug resistance and relapses, which lead to increased mortality.

Yeonjoo Hwang, BS, Staff Research Associate, University of California, San Francisco, and colleagues investigated resistance mechanisms in patients with FGFR2 fusion–positive intrahepatic cholangiocarcinoma (CCA).

The results were presented at the 2020 American Association for Cancer Research annual meeting.

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. Previous work has established, however, that it is becoming increasingly apparent that individual tumors may achieve drug resistance via multiple routes simultaneously.

Ms Hwang and colleagues used a phosphoproteomic (a branch of proteomics that identifies, catalogs, and characterizes proteins containing 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).

Ms Hwang and colleagues 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.

The AKT pathway is important, because AKT is a key effector in PKN2-mediated FGFR resistance. When AKT is activated it upregulates the NF-κB pathway, potentially leading to cell survival despite FGFR inhibition.

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

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