Abstract A48: Crosstalk between ERK2 and Akt1 in tumor cells with constitutive K-RAS activity leads to the limited response to PI3K inhibition

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Abstract Constitutive K-RAS activity in K-RAS mutated (K-RASmut) non-small cell lung cancer (NSCLC) cells leads to resistance to EGFR targeting strategies. Analyzing the K-RAS activity status revealed that a constitutive high K-RAS activity is observed not only in K-RASmut NSCLC cells but also in head and neck squamous cell carcinoma (HNSCC) cells presenting K-RAS wild-type (K-RASwt) overexpression. Similar to K-RAS-mutated NSCLC cells, increased K-RAS activity in HNSCC cells overexpressing K-RASwt was associated with the stimulated production of the EGFR ligand amphiregulin and resistance to EGFR tyrosine kinase (EGFR-TK) inhibitors such as erlotinib. Overexpression of mutated K-RAS in HNSCC cells expressing low level of K-RASwt stimulated Akt1 phosphorylation and increased clonogenic activity. Conversely, knockdown of K-RAS in K-RASmut NSCLC cells and in HNSCC cells presenting overexpression of K-RASwt resulted in sensitization to the anti-clonogenic activity of erlotinib. K-RAS activity results in both EGFR-dependent and EGFR-independent Akt1 activity. Short-term treatment (2 h) of cells with EGFR-TK or PI3K inhibitors (erlotinib and PI-103) resulted in repression of Akt1 activation, whereas long-term treatment (24 h) with inhibitors led to reactivation of Akt1 and stimulated clonogenicity. Akt1 re-activation was MAPK-ERK2-dependent and associated with a lack of complete response to anti-clonogenic activity of PI-103. A complete response was observed when PI-103 was combined with MEK inhibitor PD98059. Together, inhibition of clonogenicity in tumor cells presenting constitutive K-RAS activity independent of K-RAS mutational status can be achieved by the combination of PI3K and MAPK inhibitors. Supported by grants from the Deutsche Forschungsgemeinschaft [Ro527/5-1 and SFB-773-TP B02] and the Federal Ministry of Research and Education(BMBF grants 0258416, 03NUK006D) awarded to HPR as well as GRK 1302/2 (T11) awarded to MT/HPR. Citation Format: Mahmoud Toulany, H. Peter Rodemann. Crosstalk between ERK2 and Akt1 in tumor cells with constitutive K-RAS activity leads to the limited response to PI3K inhibition. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A48.