Targeting p38 alpha and p38 delta kinases differentially modulates responses to cisplatin and EGFR inhibitor therapies in human squamous cell carcinoma (SCC)

Cisplatin and EGFR inhibitors are frequently used as treatments for advanced stage cutaneous and head and neck SCC, however limited efficacy, toxicity, and development of resistance to these treatments restrict their clinical impact. Therefore, identifying targets for new therapies and designing strategies to overcome resistance are sorely required. p38 kinases orchestrate adaptive responses to stress and thus could function to promote the emergence of therapy-resistant phenotypes. Overexpression and/or activation of p38 alpha and p38 delta, the two main p38 isoforms in human SCC, suggest tumor-promoting functions for these kinases in squamous carcinogenesis. However, the specific contexts in which targeting them is beneficial for cancer therapy have yet to be elucidated. We recently showed that pharmacologic or genetic p38 alpha/p38 delta co-inhibition caused apoptosis in oral SCC9 and skin SCC12 cell lines, but not in normal human keratinocytes. Here we examined whether p38 alpha and p38 delta kinases function to modulate the responses of human SCC cells to treatment with cisplatin or EGFR inhibitor AG1478. Our data show that p38 alpha/p38 delta co-inhibition, but not p38 alpha inhibition alone, significantly attenuated growth-inhibitory effects of cisplatin in SCC12 cells, while enhancing those effects in SCC9 cells. Thus, p38 delta is pivotal to anti-cancer action of cisplatin in SCC12, yet promotes resistance to cisplatin in SCC9, via differential effects on ERK1/2, mTOR, and HSP90 signaling pathways in these cell lines. Furthermore, in combination with AG1478, p38 alpha/p38 delta co-inhibition, but not p38 alpha inhibition alone, led to a synergistic suppression of cell viability in SCC12 cells, suggesting that a combined blockade of the EGFR and p38 delta signaling holds promise to overcome EGFR targeted therapy resistance. Together, these data reveal disparate and context-dependent novel effects of targeting p38 signaling in human SCC