Activation of AMP-activated protein kinase sensitizes lung cancer cells and H1299 xenografts to erlotinib

Abstract

OBJECTIVES: The therapeutic scheme for non-small cell lung cancer (NSCLC) patients can be improved if adapted to the individual response. For example, 60-70% of adenocarcinoma patients show response to EGFR-tyrosine kinase inhibitors in the presence of mutated EGFR. We searched for additional target molecules involved in the action of the EGFR-tyrosine kinase inhibitor erlotinib in the absence of EGFR mutations, which might be suitable for combinatorial therapy approaches. MATERIALS AND METHODS: Erlotinib-response associated proteins were investigated in patient-derived NSCLC mouse xenografts by reverse-phase protein array technology (RPPA) and Western blotting. A combinatorial treatment approach was carried out in NSCLC cell lines and H1299 mouse xenografts, and subsequently analyzed for consequences in cell growth and signal transduction. RESULTS: AMP-activated protein kinase (AMPK) expression was increased in erlotinib responders before and after treatment. In a combinatorial approach, activation of AMPK by A-769662 and erlotinib treatment showed a synergistic effect in cell growth reduction and apoptosis activation in H1299 cells compared to the single drugs. AMPK pathway analyses revealed an effective inhibition of mTOR signaling by drug combination. In H1299 xenografts, the tumor size was significantly decreased after combinatorial treatment. CONCLUSION: Our results suggest that AMPK activation status affects response to erlotinib in distinct lung tumor models

In vitro prediction of the efficacy of molecularly targeted cancer therapy by Raman spectral imaging

“…In contrast to lipid droplets, the Raman difference spectra revealed negative peaks for the membrane, cytoplasm, and nucleus on erlotinib treatment, implying that the Raman intensity of these components is increased in erlotinib-treated cells. This is perhaps due to an increase in the expression level of proteins during apoptosis on erlotinib treatment [ 68 , 69 , 76 ].

Fig.

…”

Epithelial growth factor receptor tyrosine kinase inhibitors alleviate house dust mite allergen Der p2‐induced IL‐6 and IL‐8

“…In the present study, we found that STO‐609 remains the same as IL‐6, and down‐regulation of IL‐8 is induced by HDM. Response to Tarceva and protein profiles in before and after treatment nonsmall cell lung cancer (NSCLC) models have suggested that AMPK is a putative target protein, while AMPK activation status impacts EGFR targeted drug response . No previous study has discussed the impact of EGFR‐TKI on AMPK pathway.…”

Association of calcium/calmodulin-dependent protein kinase kinase1 rs7214723 polymorphism with lung cancer risk in a Chinese population

“…Moreover, Williams et al [ 8 ] demonstrated that the activation of CAMK (CAMK II and CAMK IV) inhibits cell cycle progression in small cell lung carcinoma (SCLC) cells. Furthermore, Hulsmann et al revealed that the activation of mitogen-activated protein kinase (MAPK) contributes to growth inhibition and apoptosis in human LC cells [ 9 ]. There is a wide consensus that CAMKK has been shown to undergo autophosphorylation and contains two isoforms (CAMKK1 and CAMKK2) [ 10 ].…”