Is the Canonical RAF/MEK/ERK Signaling Pathway a Therapeutic Target in SCLC?

Abstract

The activity of the RAF/MEK/ERK signaling pathway is critical for the proliferation of normal and cancerous cells. Oncogenic mutations driving the development of lung adenocarcinoma often activate this signaling pathway. In contrast, pathway activity levels and their biological roles are not well established in small cell lung cancer (SCLC), a fast-growing neuroendocrine lung cancer subtype. Here we discuss the function of the RAF/MEK/ERK kinase pathway and the mechanisms leading to its activation in SCLC cells. In particular, we argue that activation of this pathway may be beneficial to the survival, proliferation, and spread of SCLC cells in response to multiple stimuli. We also consider evidence that high levels of RAF/MEK/ERK pathway activity may be detrimental to SCLC tumors, including in part by interfering with their neuroendocrine fate. On the basis of these observations, we examined when small molecules targeting kinases in the RAF/MEK/ERK pathway may be useful therapeutically in patients with SCLC, including in combination with other therapeutic agents.

Keywords: Combination therapy; ERK1/2; GPCR; MAPK; SCLC; Signaling.

Figure 1

A. Schematic representation of the canonical RAS-MEK-ERK pathway and its upstream activators relevant to SCLC (see text). Specific mall molecule inhibitors are available for each kinase in this pathway. All these activators of ERK1/2 activity may have some beneficial effects for the tumors. B. Expression of genes coding for members of the canonical RAS-RAF-MEK-ERK pathway in human SCLC tumors (RNA-Seq data from ). All the genes are expressed at detectable levels, with lower levels for EGFR and BRAF. ASCL1, CgA (Chromogranin A) and ENO2 (neuron-specific enolase, NSE) are classical neuroendocrine markers for SCLC.

Figure 2

A. Summary of gene alterations (A) and copy number variations (CNV) (B) in human primary SCLC from three genomics studies ^–. Note the rarity of alterations in upstream regulators of ERK1/2.

Figure 3

Signaling networks activating the canonical RAF-MEK-ERK signaling pathway and that have been involved in SCLC metastasis (see text).