Multicenter Phase II Study of the Oral MEK Inhibitor, CI-1040, in Patients With Advanced Non-Small-Cell Lung, Breast, Colon, and Pancreatic Cancer

Abstract

CI-1040 was generally well tolerated but demonstrated insufficient antitumor activity to warrant further development in the four tumors tested. PD 0325901, a second generation MEK inhibitor, has recently entered clinical development and, with significantly improved pharmacologic and pharmaceutical properties compared with CI-1040, it may better test the therapeutic potential of MEK inhibition in cancer.

The cell cycle and cancer

“…Many of these mutations have been identified in growth signalling pathways, leading to the development of small-molecule inhibitors (SMIs) targeting cell-surface receptors and signalling molecules (eg EGFR, VEGF, KRAS, BRAF, PI3K, MEK, ERK) [15,30,[119][120][121]. This is driving the concept that, rather than describing cancers according to their site of origin and clinicopathological parameters, tumours might alternatively be classified in terms of the main pathways that drive tumour cell proliferation (eg PI3K-PTEN-mTOR-driven cancer, Wnt-driven cancer, etc.)…”

Ki67 expression levels are a better marker of reduced melanoma growth following MEK inhibitor treatment than phospho-ERK levels

“…In light of this, a number of research groups and pharmaceutical companies have begun to explore whether targeting the BRAF/MEK pathway using shRNA and small molecule inhibitors are viable therapeutic approaches (Hingorani et al, 2003;Karasarides et al, 2004;Sharma et al, 2005). In a recent series of clinical trials of MEK inhibitors, investigators have used tumour phospho-ERK (pERK) levels as a biomarker (Rinehart et al, 2004;Lorusso et al, 2005). These studies have demonstrated that although the MEK inhibitors, such as CI-1040 and PD0325901, inhibit constitutive pERK activity within tumours there was little clinical activity.…”

Elevated expression of ERK 2 in human tumor cells chronically treated with PD98059

“…3 and 4), suggesting that upregulated ERK 2 was responsible for the decreased sensitivity to PD98059 in ACHN (PD) cell and DU145 (PD) cells and these phenotype was different from the CI-1040-resistant colon 26 cell line. Although treatment with CI-1040 downregulated the activated ERK in both xenograft animal models [6] and clinical trials [8], the ERK assays used in these studies were normalized by the amount of protein, not by the cell number. Thus, in vivo, upregulation of ERK expression by tumor cells may occur after several weeks of treatment.…”

“…It has been shown that MEK inhibitors potently blocked the tumor progression in xenografted animal models [6,7]. However, MEK inhibitors did not affect human tumors in clinical trials [8,9].To address the question of how human tumor cells evade the inhibitory action of MEK inhibition at a cellular level, we examined the effects of chronic exposure to PD98059 on human tumor cells. We show here for the first time that the chronic exposure of tumor cells to a MEK inhibitor upregulated the expression of ERK 2, which was involved in the decreased sensitivity of their proliferation to MEK inhibitor-treatment.…”

“…It has been shown that MEK inhibitors potently blocked the tumor progression in xenografted animal models [6,7]. However, MEK inhibitors did not affect human tumors in clinical trials [8,9].…”