Abstract 4478: 6-Phosphofructo-2-Kinase (PFKFB3): At the crossroads of resistance to targeted cancer therapies

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Abstract Targeted cancer therapies that block the growth and spread of cancer by interfering with specific onco-proteins are limited by signaling mechanisms that drive intrinsic and acquired resistance. In particular, the MAPK and the PI3K/AKT pathways have been found to both reduce response rates to these agents and to mediate the acquisition of resistance via mutations that activate both pathways. For example, two recently approved BRAFV600E inhibitors, vemurafenib and dabrafenib, cause dramatic clinical responses in ∼50% of BRAFV600E + melanoma patients but universally become ineffective within 5-6 months as a result of genetic alterations that activate the MAPK and PI3K-AKT pathways, including amplifications in BRAFV600E, loss of PTEN, and activating mutations in NRAS and KRAS, MEK, AKT1/3, PIK3CA and PIK3CG. Several of these mutated signaling proteins stimulate glucose metabolism, required for survival and proliferation, in part by increasing the expression and activity of 6-phosphofructo-2-kinase (PFKFB3). For example, PFKFB3 transcription is induced by HIF-1α (which is increased by BRAFV600E, RAS and MEK), loss of PTEN, and PFKFB3 activity is stimulated by AKT via phosphorylation of serine 461. We postulated that PFKFB3 is an essential downstream target of targeted cancer therapies and that the multitude of mutations and amplifications in signaling pathways that cause resistance to these agents activate PFKFB3. In new studies, we demonstrate that BRAFV600E, estradiol and epidermal growth factor each regulate PFKFB3 expression in melanoma cells, breast cancer cells and NSCLC cells, respectively. Moreover, we find that simultaneous inhibition of these oncoproteins or their co-ligands (i.e. the estrogen and EGF receptors) and PFKFB3 using a novel PFKFB3 inhibitor currently in a phase 1 trial, PFK-158, causes a synergistic increase in apoptosis and cytotoxicity in vitro, suggesting that PFK-158 can overcome the intrinsic resistance to these agents. We then decided to determine if these significant synergies would translate in vivo by investigating them in the A375 and A2058 melanoma preclinical models, and in the MCF-7 ER-dependent breast model. For instance, we compared the anti-tumor effects in A375 melanoma xenograft-bearing mice of: (i) the BRAFV600E inhibitor vemurafenib; (ii) PFK-158; or (iii) the combination of vemurafenib and PFK-158. Although we observed significant tumor growth inhibition with both monotherapies (>80%), we only observed tumor regression with the combination therapy (>50%). Results in these different models will be presented. Taken together, these data demonstrate that the PFKFB3 inhibitor PFK-158 may be able to universally overcome resistance to targeted cancer therapies. Furthermore, we predict that phase 1/2 trials of PFK-158 in combination with targeted cancer agents will yield improvements in objective response rates as well as improvements in progression-free survival. Citation Format: Sucheta Telang, Julie O'Neal, Yoannis Imbert-Fernandez, Brian Clem, Nadiia Lypova, Gilles H. Tapolsky, John Trent, Jason Chesney. 6-Phosphofructo-2-Kinase (PFKFB3): At the crossroads of resistance to targeted cancer therapies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4478. doi:10.1158/1538-7445.AM2015-4478