Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33

Guo

Molecular Cancer Therapeutics

et al. 2016

Oncogenic mutations of KRAS pose a great challenge in the treatment of colorectal cancer. Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the HSP90 inhibitor AUY922 than those carrying wild-type KRAS. Although AUY922 inhibited HSP90 activity with comparable potency in colon cancer cells irrespective of their KRAS mutational statuses, those with mutant KRAS were markedly more sensitive to AUY922-induced apoptosis. This was associated with upregulation of the BH3-only proteins Bim, Bik, and PUMA. However, only Bim appeared essential, in that knockdown of Bim abolished, whereas knockdown of Bik or PUMA only moderately attenuated apoptosis induced by AUY922. Mechanistic investigations revealed that endoplasmic reticulum (ER) stress was responsible for AUY922-induced upregulation of Bim, which was inhibited by a chemical chaperone or overexpression of GRP78. Conversely, siRNA knockdown of GRP78 or XBP-1 enhanced AUY922-induced apoptosis. Remarkably, AUY922 inhibited the growth of mutant KRAS colon cancer xenografts through activation of Bim that was similarly associated with ER stress. Taken together, these results suggest that AUY922 is a promising drug in the treatment of mutant KRAS colon cancers, and the agents that enhance the apoptosis-inducing potential of Bim may be useful to improve the therapeutic efficacy.

Section: Discussionmentioning

confidence: 86%

Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress

Guo

Molecular Cancer Therapeutics

et al. 2016

“…For example, only depletion of the entire STK33 protein through HSP90 inhibition, but not selective inhibition of STK33's enzymatic activity was able to reproduce the impressive effects of RNA interference-mediated knockdown, suggesting different functions of STK33 are involved in the synthetic lethal interaction with oncogenic KRAS. 46,47 Here we present a different strategy named synthetic lethal vulnerability. Whereas inhibition of the alt-NHEJ pathway has no effect in KRAS mutant cells, it is able to sensitize malignant cells to genotoxic agents.…”

Section: Discussionmentioning

confidence: 99%

Targeting components of the alternative NHEJ pathway sensitizes KRAS mutant leukemic cells to chemotherapy

Hähnel

Enders

Sasca

et al. 2014

Blood

Key Points• Oncogenic KRAS causes upregulation of components of the alt-NHEJ pathway, thereby promoting genomic instability.• Inhibition of the alt-NHEJ pathway selectively sensitizes KRAS-mutant leukemic cells to cytotoxic agents.Activating KRAS mutations are detected in a substantial number of hematologic malignancies. In a murine T-cell acute lymphoblastic leukemia (T-ALL) model, we previously showed that expression of oncogenic Kras induced a premalignant state accompanied with an arrest in T-cell differentiation and acquisition of somatic Notch1 mutations. These findings prompted us to investigate whether the expression of oncogenic KRAS directly affects DNA damage repair. Applying divergent, but complementary, genetic approaches, we demonstrate that the expression of KRAS mutants is associated with increased expression of DNA ligase 3a, poly(ADP-ribose) polymerase 1 (PARP1), and X-ray repair cross-complementing protein 1 (XRCC1), all essential components of the error-prone, alternative nonhomologous end-joining (alt-NHEJ) pathway. Functional studies revealed delayed repair kinetics, increased misrepair of DNA double-strand breaks, and the preferential use of microhomologous DNA sequences for end joining. Similar effects were observed in primary murine T-ALL blasts. We further show that KRAS-mutated cells, but not KRAS wild-type cells, rely on the alt-NHEJ repair pathway on genotoxic stress. RNA interference-mediated knockdown of DNA ligase 3a abolished resistance to apoptotic cell death in KRAS-mutated cells. Our data indicate that targeting components of the alt-NHEJ pathway sensitizes KRAS-mutated leukemic cells to standard chemotherapeutics and represents a promising approach for inducing synthetic lethal vulnerability in cells harboring otherwise nondruggable KRAS mutations. (Blood. 2014;123(15):2355-2366

Pharmacological Research

“…A particular molecular chaperone of interest is heat shock protein 90 (Hsp90), which has been shown to support aberrant expression of key oncoproteins such as ALK (anaplastic lymphoma kinase), BCR-ABL (break point cluster-Abelson tyrosine kinase) BRAF (serine/threonine-protein kinase B-Raf), CDK4 (cyclindependent kinase 4), CRAF (serine/threonine-protein kinase C-Raf), HER2 (human epidermal growth factor receptor 2), JAK2 (Janus kinase 2), KIT (Mast/stem cell growth factor receptor, protooncogene c-Kit) MET (mesenchymal epithelial transition factor), and STK33 (serine/threonine kinase 33) [13][14][15][16][17]. Initial attempts to target Hsp90 with inhibitors that resemble the structure of the natural products geldanamycin and radicicol indicated that successful targeting of the chaperone could yield therapeutic benefit at the clinical level, but such compounds are plagued by unfavorable toxicity profiles that limit achievable doses [18,19].…”

Section: Introductionmentioning

confidence: 99%

PU-H71: An improvement on nature's solutions to oncogenic Hsp90 addiction

Trendowski

2015

Despite recent advances in precision medicine, many molecular-based antineoplastic agents do not potentiate sustainable long term remissions, warranting the investigation of novel therapeutic strategies. Heat shock protein 90 (Hsp90) is a molecular chaperone that not only has oncogenic properties, but also has distinct expression profiles in malignant and normal cells, providing a rational strategy to attain preferential damage. Prior attempts to target Hsp90 with natural product-based compounds have been hampered by their associated off target toxicities, suggesting that novel, fully synthetic inhibitors may be required to achieve the specificity necessary for therapeutic efficacy. Therefore, this review highlights the antineoplastic potential of PU-H71 (8-[(6-iodo-1,3-benzodioxol-5-yl)sulfanyl]-9-[3-(propan-2-ylamino)propyl]purin-6-amine), a novel purine based analog that has shown efficacy in many preclinical models of malignancy, and is now under clinical examination. In addition, the review suggests potential concomitant therapeutic approaches that may be particularly beneficial to molecular-based, as well as traditional cytotoxic cancer chemotherapy.