The Role of RAF1 Amplifications as Drivers of a Subset of Bladder Cancers - Expert Commentary

RAF kinases are critical proteins in the MAPK cascade, essential for cancer cell processes such as proliferation and migration. RAF1 functions as an obligate homodimer or heterodimer with BRAF. The role of RAF1 amplifications as drivers or therapeutic targets in bladder cancer is unclear.


A recently published study by Bekele et al. in the Journal of Clinical Investigation investigated the role of RAF1 amplifications in bladder cancer. The authors used the TCGA bladder cancer cohort to find that RAF1 amplifications occurred in 12% of bladder tumors and were enriched in the luminal-unstable molecular subtype. These observations were validated in another bladder cancer cohort which showed a similar proportion of RAF1 amplifications (11%). These amplifications were confirmed using fluorescence in situ hybridization (FISH).

The authors identified two bladder cancer cell lines (5637 and UMUC9) harboring RAF1 amplifications. The two cell lines were sensitive to RAF1 depletion using siRNAs or pharmacologic inhibition using a pan-RAF inhibitor. In addition, the UMUC9 cell line showed increase sensitivity to the combination of RAF and MEK inhibition. Bladder tumor xenografts treated with pan-RAF inhibitor alone or in combination with trametinib had significantly less weight than vehicle-treated tumors.

RAS proteins have distinct binding affinities to the downstream RAF proteins. Notably, HRAS preferentially binds RAF1 over BRAF. The investigators posited that the inhibition of RAF1 alone or combined with MEK inhibition will show preferential efficacy in HRAS or NRAS mutant bladder tumors. The investigators treated mice bearing NRAS mutant Ku-19-19 xenografts with pan-RAF inhibitors and trametinib. Tumors treated with pan-RAF inhibitors and trametinib had significantly less weight than vehicle-treated tumors suggesting significant anti-cancer activity.

This study highlights the promise of targeted therapies for a distinct subset of bladder tumors with focal amplification of the RAF1 in preclinical models.  Testing these therapeutic strategies could open new possibilities for patients with bladder cancer.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

  1. Bekele RT, Samant AS, Nassar AH, So J, Garcia EP, Curran CR, et al. RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics. J Clin Invest. 2021 Sep 23;doi.10.1172/JCI147849.

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