Hypoxia-Induced PIM Kinase and Laminin-Activated Integrin α6 Mediate Resistance to PI3K Inhibitors in Bone-Metastatic CRPC

Toth, Rachel K.; Tran, Jack D.; Muldong, Michelle; Nollet, Eric A.; Schulz, Veronique V.; Jensen, Corbin C.; Hazelhurst, Lori A.; Corey, Eva; Durden, Donald L.; Jamieson, Christina; Miranti, Cindy K.; Warfel, Noel A.

doi:10.1101/685602

Cited by 17 publications

(21 citation statements)

References 58 publications

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“…Our data appears to support this relationship, as it would explain the upregulation of mTOR phosphoprotein following treatment with a PIM inhibitor, or upregulation of PIM targets such as BAD phosphoprotein after treatment with BEZ235. This pathway compensation has been shown to contribute to development of resistance to PI3K inhibitors 5,33,34 . We noted that the effects of AZD-1208 and BEZ235 on gene and phosphoprotein expression often oppose each other.…”

Section: Discussionmentioning

confidence: 99%

Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer

Luszczak

Simpson

Stopka‐Farooqui

et al. 2020

Sci Rep

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PIM and PI3K/mTOR pathways are often dysregulated in prostate cancer, and may lead to decreased survival, increased metastasis and invasion. The pathways are heavily interconnected and act on a variety of common effectors that can lead to the development of resistance to drug inhibitors. Most current treatments exhibit issues with toxicity and resistance. We investigated the novel multikinase PIM/PI3K/mTOR inhibitor, AUM302, versus a combination of the PIM inhibitor, AZD-1208, and the PI3K/mTOR inhibitor BEZ235 (Dactolisib) to determine their impact on mRNA and phosphoprotein expression, as well as their functional efficacy. We have determined that around 20% of prostate cancer patients overexpress the direct targets of these drugs, and this cohort are more likely to have a high Gleason grade tumour (≥ Gleason 8). A co-targeted inhibition approach offered broader inhibition of genes and phosphoproteins in the PI3K/mTOR pathway, when compared to single kinase inhibition. The preclinical inhibitor AUM302, used at a lower dose, elicited a comparable or superior functional outcome compared with combined AZD-1208 + BEZ235, which have been investigated in clinical trials, and could help to reduce treatment toxicity in future trials. We believe that a co-targeting approach is a viable therapeutic strategy that should be developed further in pre-clinical studies. Prostate cancer remains as the leading cause of cancer-related death for men 1. Most current therapies exhibit issues with significant side effects, therefore it is crucial to develop lower toxicity therapeutics which would reduce the impact of treatment on patients' lives. Overexpression of the PIM family in prostate cancer has been found to lead to increased tumorigenicity and faster progression of the disease due to its impact on metastasis formation, invasion and migration 2-4. Clinically, PIM can lead to decreased overall survival, insensitivity to cancer treatment and increased proliferation 5. Its effect is mainly mediated by interactions with other pathways including PI3K/mTOR (Phosphoinositide 3-kinase; mammalian target of rapamycin), and various downstream effectors 2,6,7. The PI3K/mTOR pathway deregulation in cancer correlates with disease progression 8 and impacts on apoptosis, survival and cell growth 6. The PI3K pathway also regulates multiple oncogenes and tumour suppressor genes 8. Despite being an attractive pathway for anti-cancer drug targeting, results from monotherapeutic PI3K inhibition strategies have been disappointing, with the growing consensus being that improved co-targeting strategies are warranted 9-11 .

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Section: Discussionmentioning

confidence: 99%

Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer

Luszczak

Simpson

Stopka‐Farooqui

et al. 2020

Sci Rep

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“…We observed a decrease in the mRNA expression of integrins A2, A5, A6, and B1 in PC3 LN4 cells with EDC3 S161A knock‐in mutant and in PC3 LN4‐EDC3KO cells complemented with GFP EDC3 S161A when compared to their respective controls (Fig EV5E–H). Because integrins α6 and β1 have an important role in cancer progression (Sroka et al , 2016) and are a potential therapeutic target for anti‐cancer chemotherapy (Toth et al , 2019), we further focused on the expression of these two integrins. The mRNA and protein levels of integrin α6 and β1 were both reduced in PC3‐LN4 EDC3 S161A cells and in EDC3 KO cells complemented with GFP EDC3 S161A, and treatment of wild‐type cells with PIM and AKT inhibitors decreased these integrins as well (Fig 7F–J).…”

Section: Resultsmentioning

confidence: 99%

EDC3 phosphorylation regulates growth and invasion through controlling P‐body formation and dynamics

et al. 2021

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Regulation of mRNA stability and translation plays a critical role in determining protein abundance within cells. Processing bodies (P‐bodies) are critical regulators of these processes. Here, we report that the Pim1 and 3 protein kinases bind to the P‐body protein enhancer of mRNA decapping 3 (EDC3) and phosphorylate EDC3 on serine (S)161, thereby modifying P‐body assembly. EDC3 phosphorylation is highly elevated in many tumor types, is reduced upon treatment of cells with kinase inhibitors, and blocks the localization of EDC3 to P‐bodies. Prostate cancer cells harboring an EDC3 S161A mutation show markedly decreased growth, migration, and invasion in tissue culture and in xenograft models. Consistent with these phenotypic changes, the expression of integrin β1 and α6 mRNA and protein is reduced in these mutated cells. These results demonstrate that EDC3 phosphorylation regulates multiple cancer‐relevant functions and suggest that modulation of P‐body activity may represent a new paradigm for cancer treatment.

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“…Elevated integrin α6 protein expression, based on IHC staining, was previously observed in CRPC LuCaP PDX tumors. 46 Basal integrin α6 expression was higher in castration-resistant C4–2 and C4–2B cells adherent to laminin relative to their parental androgen-sensitive LNCaP cells ( Fig. 1B ).…”

Section: Resultsmentioning

confidence: 90%

“… 5 Furthermore, hypoxia directly stimulates the expression of integrin α6 and β1. 6 , 44 , 46 Thus, hypoxia-induced integrin α6β1 expression may provide an additional mechanism for prostate cancer survival upon ADT treatment.…”

Section: Introductionmentioning

confidence: 99%

Androgen receptor-induced integrin α6β1 and Bnip3 promote survival and resistance to PI3K inhibitors in castration-resistant prostate cancer

et al. 2020

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The androgen receptor (AR) is the major driver of prostate cancer growth and survival. However, almost all patients relapse with castration resistant disease (CRPC) when treated with anti-androgen therapy. In CRPC, AR is often aberrantly activated independent of androgen. Targeting survival pathways downstream of AR could be a viable strategy to overcome CRPC. Surprisingly, little is known about how AR drives prostate cancer survival. Furthermore, CRPC tumors in which Pten is lost are also resistant to eradication by PI3K inhibitors. We sought to identify the mechanism by which AR drives tumor survival in CRPC to identify ways to overcome resistance to PI3K inhibition. We found that integrin α6β1 and Bnip3 are selectively elevated in CRPC downstream of AR. While integrin α6 promotes survival and is a direct transcriptional target of AR, the ability of AR to induce Bnip3 is dependent on adhesion to laminin and integrin α6β1-dependent nuclear translocation of HIF1α. Integrin α6β1 and Bnip3 were found to promote survival of CRPC cells selectively on laminin through the induction of autophagy and mitophagy. Furthermore, blocking Bnip3 or integrin α6β1 restored sensitivity to PI3K inhibitors in Pten-negative CRPC. We identified an AR driven pathway that cooperates with laminin and hypoxia to drive resistance to PI3K inhibitors. These findings can help explain in part why PI3K inhibitors have failed in clinical trials to overcome AR-dependent CRPC.

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Hypoxia-Induced PIM Kinase and Laminin-Activated Integrin α6 Mediate Resistance to PI3K Inhibitors in Bone-Metastatic CRPC

Cited by 17 publications

References 58 publications

Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer

Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer

EDC3 phosphorylation regulates growth and invasion through controlling P‐body formation and dynamics

Androgen receptor-induced integrin α6β1 and Bnip3 promote survival and resistance to PI3K inhibitors in castration-resistant prostate cancer

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