The evaluation of downstream signaling resulting from EGFR and/or HER2 inhibition among patients with bladder cancer suggests that p38 MAPK may be a therapeutic target in this population, according to a study published in Urology.1

For this study, researchers exposed various cell lines of bladder cancer to erlotinib (an EGFR inhibitor) and lapatinib (a dual EGFR/HER2 inhibitor), and utilized phosphokinase assays and immunoblotting to analyze the impact these medications had on downstream signaling pathways.

In the first phosphokinase array, RT112 cancer cell lines were exposed to erlotinib. Analysis revealed an altered expression of 10 protein targets: overexpression of p38 MAPK, GSK-3α/β, MEK1/2, Akt, TOR, Src, p27, p27 (Thr198), p27 (Thr157), and PLCɣ-1, and a reduced expression of STAT4.

A second phosphokinase array was performed to confirm the findings of the first assay, but this time cell lines were exposed to lapatinib. Compared with the first array, only 3 of the 10 phospho-proteins previously identified had altered expression: p38 MAPK, GSK-3α/β, and STAT4.

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To validate these findings, researchers utilized Western blot analyses to assess the phosphorylation status of the affected proteins in response to erlotinib plus lapatinib. No differences were observed for GSK-3α/β and STAT4, but p38 MAPK continued to be overexpressed.

The authors hypothesized that cancer cells use increased p38 MAPK phosphorylation as a resistance mechanism in response to EGFR/HER2 inhibition. They exposed multiple cell lines to compound SB203580 — a p38 MAPK inhibitor — and discovered that there was an anti-proliferative effect. Finally, they assessed the effect of SB203580 plus lapatinib on these cell lines; the anti-proliferative effect was significantly greater in combination compared with either agent alone (P < .0001). A similar effect was observed with erlotinib.

The authors concluded that “p38 MAPK is a potential therapeutic target in bladder cancer and this strategy warrants further development in this disease.”

Reference

  1. Vidal RM, da Mota SR, Hayden A, et al. EGFR family inhibition identifies P38 MAPK as a potential therapeutic target in bladder cancer. Urology. 2017 Nov 15. doi: 10.1016/j.urology.2017.10.041 [Epub online ahead of print]