KRAS mutant lung cancer cells are differentially responsive to MEK inhibitor due to AKT or STAT3 activation: Implication for combinatorial approach

Abstract

KRAS is frequently mutated in nonsmall cell lung cancer (NSCLC), resulting in the activation of the MAPK/ERK kinase (MEK)/ERK pathway. High-throughput mutation profile has shown that lung cancer frequently harbors comutation of cancer-related genes. Therefore, given that cancer cells have multiple genetic alterations, combinatorial therapeutic strategy is demanded for effective cancer therapy. To address this, we first characterized MEK dependence in four NSCLC cells. Two cells (H358, A549) carried KRAS mutation only, and the other two (H23, H157) harbored comutation of KRAS/PTEN. H358 cells with KRAS mutation only were sensitive to MEK inhibition. However, the other KRAS mutant A549 cells were resistant to MEK inhibition. Previously, we have shown that dual inhibition of EGFR and MEK signaling shows a synergistic effect on KRAS mutant gastric cancer cells by suppressing compensatory activation of AKT. Here we also observed that this combination was effective in KRAS mutant A549 cells. However, the combination was ineffective in H23 and 157 cells with comutation of KRAS/PTEN. Compared to KRAS mutant/PTEN wild-type cells, signal transducer and activator of transcription 3 (STAT3) was significantly activated following MEK inhibition in KRAS/PTEN comutant cells. Combined STAT3 inhibition by a JAK2 inhibitor or gene knockdown with MEK inhibition blocked STAT3 activation, synergistically suppressed cell growth, and induced apoptosis in comutant cells. Taken together, our study provides molecular insights that help explain the heterogeneous response to MEK inhibition in KRAS mutant lung cancers, and presents a rationale for the clinical investigation of combination of MEK and EGFR inhibitor or MEK and JAK2 inhibitor depending on PTEN status.

The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma

“…10,14,[18][19][20][21][22][23] AZD6244 is a benzimidazole and selective 2nd generation MEK inhibitor with reported activity at nanomolar concentrations against purified MEK1 enzyme in preclinical solid tumor studies. [18][19][20][21][22][23] Further, AZD6244 is a noncompetitive MEK inhibitor with preclinical antitumor activity in solid tumor models including hepatocellular, colon, myeloma, thyroid, pancreatic, melanoma, and breast cancers 19,20,41 and tested clinically in phase 1 24 and phase 2 trials of advanced, refractory colorectal, melanoma, and lung cancer. [25][26][27] AZD6244 has been examined in leukemia and myeloma models, [42][43][44] however to our knowledge, has never been tested in lymphoma.…”

“…15,17 ARRY-142886 (AZD6244, selumetinib; Astra Zeneca) is a selective nonATP-competitive 2nd generation oral MEK inhibitor studied primarily in solid tumor studies with reported nanomolar activity against purified MEK1 enzyme. [18][19][20][21][22][23] Furthermore, phase 1 and phase 2 solid tumor clinical trials have shown this agent to be well-tolerated and have encouraging clinical efficacy. [24][25][26][27] To our knowledge, minimal data are available on newer generation MEK inhibitors in lymphoma and moreover, this anti-MEK agent has never been examined in lymphoma.…”

Molecular pathology of lung cancer: key to personalized medicine

“…The ligand binding-induced dimerization results in cross-autophosphorylation of key tyrosine residues in the cytoplasmic domains, which function as docking sites for downstream signal transducers. 36 This activation of EGFR initiates signaling cascades involving several downstream pathways, which induce crucial cellular responses, such as proliferation, differentiation, motility, and survival 13,[52][53][54][55][56][57][58][59][60][61][62] (Figure 1).…”

“…56,216 The histological phenotype of BRAF mutant adenocarcinomas has not been well described, but was reported to be a mixed type adenocarcinoma with a high incidence of papillary (80%) and lepidic growth (50%) patterns. 217 De Oliveira Duarte Achcar et al 218 investigated 15 primary micropapillary lung adenocarcinomas for KRAS, EGFR, and BRAF mutations.…”

RAF-MEK-MAPK Pathway Targeted by Tumor Suppression and Anticancer Therapeutic Agents

“…The dual inhibition of MEK and EGFR or MEK and signal transducer and activator of transcription 3 (STAT3) signaling pathways may constitute a potent therapeutic strategy for the treatment of KRAS mutant NSCLCs. But AZD6244 displays insufficient efficacy in non-small cell lung cancers (NSCLCs) due to deregulated expression and/or mutations of PIK3CA and PTEN [59][60][61][62][63]. A rational basis has been validated for choosing the inhibitor to best combine with the MEK inhibitor in cells on the basis of the expression and mutations of several oncogenes [64][65][66][67][68][69][70][71][72][73][74].…”