Abstract IA2-2: Targeting redundancy in RAS-PI3K signaling in NSCLC

Cytotoxic chemotherapy has formed the backbone of cancer treatment for decades. The clinical use of such agents was established using dosing strategies that favored efficacy (optimal tumor regression) coupled with minimal toxicity. Conceptually, little regard was given to mechanisms governing survival circuitry, or the genetic alterations in a given tumor, which we now appreciate, are important prognosticators of clinical response for both cytotoxic drugs and therapies that target aberrant signaling pathways involved in cancer pathogenesis. Pharmacogenomic profiling is focused on characterizing genetic changes in tumor cells that drive malignant growth and render cells ‘addicted’ to certain pathways for survival and growth. By identifying these genes and the pathways in which they participate, one can devise therapeutic strategies to disable them. An underappreciated fact in cancer therapeutics is that cancer cells respond to and counteract the effects of any drugs that threaten their survival. Signaling pathways have evolved with innate adaptive abilities to form a regulatory circuitry via positive and negative feedback. These adaptive properties present in normal cells are exploited further in cancer genomes due to their genomic instability and the resulting plasticity. The MAPK-RAS-PI3K signaling network is oncogenic in many human malignancies, including NSCLC, though somatic mutations in PI3K are rare in this disease. Efforts to therapeutically target MAPK dysfunction have been focused on RAF and RAS, since their high frequency of mutations in human tumors renders these druggable targets (activating point mutations in K-RAS occur in approximately 30% of lung adenocarcinomas). Therapeutic strategies to inhibit oncogenic RAS alone have not been successful since these have focused on disrupting effectors downstream of the canonical RAS pathway, without perturbing other RAS effectors. One such RAS- binding protein is type I PI3K, which is required for RAS-driven tumorigenesis: therefore, the PI3K / mTOR component is an important target in RAS-mutant tumors. Therapies directed at MEK, a downstream RAS effector, have been in therapeutic development and shown to exhibit optimal singleagent activity in RAF-mutant tumors. However, the enthusiasm for their clinical application in lung cancer is moderated by the low prevalence of RAF mutations/amplifications in the disease and the appreciation that there is significant redundancy in the MAPK-PI3K pathway that mediates acute resistance to these agents. Therefore, like most targeted therapies, the optimal use for this drug will be in combination. The plasticity of cancer cell circuitry is an important consideration in the rational design of drug combinations, particularly those targeting this signaling network. By characterizing the mechanisms that RAS and RAF mutant cancer cells use to escape MEK-inhibitor therapy, one can use combinations of drugs that target addicted pathways and also prevent cancer cells activating secondary pathways to evade death. We have focused on strategies to counteract these mechanisms of resistance and exploit them therapeutically. An example of this is using MEK inhibitors with rapamycin, which is synergistic in a diverse range of NSCLC cell lines and xenograft models. We have identified proteins in the RAS-PI3K network that moderate the therapeutic response to the MEK-rapamycin combination. In addition, other combinations of MEK inhibitors with drugs that target the estrogen receptor and erbB receptor tyrosine kinases, respectively, will be discussed. Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA2-2.