Blocking p38/ERK crosstalk affects colorectal cancer growth by inducing apoptosis in vitro and in preclinical mouse models

Sorafenib inhibits p38α activity in colorectal cancer cells and synergizes with the DFG-in inhibitor SB202190 to increase apoptotic response

“…4,[6][7][8] Furthermore, p38α inhibition by type-I or type-II compounds induces increased expression of the RTK receptor HER3 in a FoxO3A-and Sirt1-dependent manner, thus leading to MEK/ ERK overactivation in CRC cells and tissues. 5 Of note, inhibition of MEK1 triggers the phospho-activation of p38, indicating the existence of a p38α/ERK crosstalk in CRC cells, which is independent from the mutational status of KRAS and BRAF. Indeed, these MEK/ERK upstream kinases have been found overactive in 50% of CRC patients, 9 and BRAF and MEK1 inhibitors exert anticancer effects in cell lines and xenografted tumors.…”

“…12 Combined inhibition of p38α and MEK by type-I ligands specifically fosters cell death by inducing apoptosis to a higher extent than either single treatment in CRC cell lines, in CRC xenografted nude mice and in the AOM/DSS colitis-associated carcinoma mouse preclinical model. 5 At the molecular level, inhibition of p38α causes transcriptional upregulation of TRAIL and activation of caspase-8, while concomitant MEK inhibition triggers Bax-dependent apoptosis by enabling signaling propagation through t-Bid and caspase-3. 5 These data, which have been validated in preclinical models, emphasize the therapeutic potential of combined inhibition of p38α and MEK and suggest that the cross-talk between p38α and ERK may play an important, reciprocal and compensatory role in CRC progression and cell survival.…”

“…5 At the molecular level, inhibition of p38α causes transcriptional upregulation of TRAIL and activation of caspase-8, while concomitant MEK inhibition triggers Bax-dependent apoptosis by enabling signaling propagation through t-Bid and caspase-3. 5 These data, which have been validated in preclinical models, emphasize the therapeutic potential of combined inhibition of p38α and MEK and suggest that the cross-talk between p38α and ERK may play an important, reciprocal and compensatory role in CRC progression and cell survival. Thus, a single agent targeting both pathways could represent a useful tool in CRC therapy.…”

“…Valentina Grossi, 1 Micaela Liuzzi, 2 stefania Murzilli, 3,4 Nicola Martelli, 3,5 anna Napoli, 2 Giuseppe Ingravallo, 2 alberto Del Rio 6 * and Cristiano simone 7,8, cascades. 3 However, difficulties in achieving appropriate selectivity profiles increased the interest in the design of new inhibitors capable of targeting specific conformations and/or allosteric sites.…”

“…4 Moreover, we found high levels of phospho-activated p38 in a subset of high-grade human CRC specimens. 5 In CRC cells, p38α sustains the expression of HIF1α target genes encoding for glycolytic rate-limiting enzymes, and its blockade by type-I inhibitors (i.e., compounds that target the DFG-in conformation) causes a drastic decrease in ATP intracellular levels. Pharmacologic or genetic inactivation of p38α triggers AMPK-mediated activation of FoxO-dependent transcription, leading to autophagy, cell clinical trials, 13,17 most probably because of its inability to completely impair p38α activity.…”