Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal most cancers cells.

Little AS, Balmanno K, Sale MJ, Newman S, Dry JR, Hampson M, Edwards PA, Smith PD, Cook SJ. "Sci Signal. 2011 Mar"

The acquisition of resistance to protein kinase inhibitors is actually a expanding difficulty in most cancers therapy. We modeled acquired resistance towards the MEK1/2 (mitogen-activated or extracellular signal-regulated protein kinase, kinases one and 2) inhibitor AZD6244 (Selumetinib, ARRY-142886) in colorectal cancer cell lines harboring mutations in BRAF (COLO205 and HT29 lines) or KRAS (HCT116 and LoVo lines).

Selumetinib-resistant derivatives had been refractory to Selumetinib-induced cell cycle arrest and demise and exhibited a marked boost in ERK1/2 (extracellular signal-regulated kinases 1 and 2) pathway signaling and cyclin D1 abundance when assessed inside the absence of inhibitor.

Inhibition of BRAF reversed resistance to ARRY-142886 in COLO205 cells, which suggested that mixed inhibition of MEK1/2 and BRAF may possibly lessen the likelihood of acquired resistance in tumors with BRAF(600E). Knockdown of KRAS reversed ARRY-142886 resistance in HCT116 cells as well as lowered the activation of ERK1/2 and protein kinase B; nevertheless, the combined inhibition of ERK1/2 and phosphatidylinositol 3-kinase signaling had little impact on ARRY-142886 resistance, suggesting that additional KRAS effector pathways contribute to this procedure.

Genomic sequencing unveiled no acquired mutations in MEK1 or MEK2, the primary target of ARRY-142886. Relatively, resistant lines showed a marked up-regulation of their respective driving oncogenes, BRAF(600E) or KRAS(13D), as a result of intrachromosomal amplification.

Microarray analysis recognized elevated expression of an 18-gene signature previously identified as reflecting MEK1/2 pathway output in resistant cells. Therefore, amplification with the driving oncogene (BRAF(600E) or KRAS(13D)) can drive acquired resistance to MEK1/2 inhibitors by increasing signaling by way of the ERK1/2 pathway. Even so, up-regulation of KRAS(13D) results in activation of several KRAS effector pathways, underlining the therapeutic challenge posed by KRAS mutations.