byl719 and navitoclax

Estrogen dependence is major driver of ER + breast cancer, which is associated with PI3K mutation. PI3K inhibition (PI3Ki) can restore dependence on ER signaling for some hormone therapy-resistant ER + breast cancers, but is ineffective in others. Here we show that short-term supplementation with estrogen strongly enhanced Pik3caH1047R-induced mammary tumorigenesis in mice that resulted exclusively in ER + tumors, demonstrating the cooperation of the hormone and the oncogene in tumor development. Similar to human ER + breast cancers that are endocrine-dependent or endocrine-independent at diagnosis, tumor lines from this model retained ER expression but were sensitive or resistant to hormonal therapies. PI3Ki did not induce cell death but did cause upregulation of the pro-apoptotic gene BIM. BH3 mimetics or PI3Ki were unable to restore hormone sensitivity in several resistant mouse and human tumor lines. Importantly however, combination of PI3Ki and BH3 mimetics had a profound, BIM-dependent cytotoxic effect in PIK3CA-mutant cancer cells while sparing normal cells. We propose that addition of BH3 mimetics offers a therapeutic strategy to markedly improve the cytotoxic activity of PI3Ki in hormonal therapy-resistant and ER-independent PIK3CA-mutant breast cancer.

Topics: Aniline Compounds; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; BH3 Interacting Domain Death Agonist Protein; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Cocarcinogenesis; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Estradiol; Estrogen Receptor alpha; Female; Fulvestrant; Gene Expression Regulation, Neoplastic; Gene Knock-In Techniques; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Mutation, Missense; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Neuropeptides; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Sulfonamides; Thiazoles

Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis, and mitosis, offering attractive targets for anticancer treatment. Using unbiased combination screening in a large panel of cancer cell lines, we have identified a strong synergy between TNKS and MEK inhibitors (MEKi) in KRAS-mutant cancer cells. Our study uncovers a novel function of TNKS in the relief of a feedback loop induced by MEK inhibition on FGFR2 signaling pathway. Moreover, dual inhibition of TNKS and MEK leads to more robust apoptosis and antitumor activity both in vitro and in vivo than effects observed by previously reported MEKi combinations. Altogether, our results show how a novel combination of TNKS and MEK inhibitors can be highly effective in targeting KRAS-mutant cancers by suppressing a newly discovered resistance mechanism.

Topics: Acetamides; Aminopyridines; Aniline Compounds; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Drug Synergism; Erlotinib Hydrochloride; Feedback, Physiological; Female; Humans; MAP Kinase Kinase Kinases; Mice; Mice, Nude; Morpholines; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Pyrimidinones; Quinazolines; ras Proteins; Receptor, Fibroblast Growth Factor, Type 2; Signal Transduction; Sulfonamides; Tankyrases; Thiazoles; Xenograft Model Antitumor Assays