Insulin Receptor Conveys Intrinsic Resistance to IGF-1R Targeted Therapy

Increased signaling through the insulin-like growth factor (IGF) pathway has been implicated in the progression of several types of human cancers. The type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinase is an important mediator of the protumorigenic effects of IGF-I/II, and inhibitors of IGF-1R signaling are currently being tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target. Despite mounting evidence that the highly homologous insulin receptor (IR) can also convey protumorigenic signals, its direct role in cancer progression has not been genetically defined in vivo, and it remains unclear whether such a role for IR signaling could compromise the efficacy of selective IGF-1R targeting strategies.

Studies of Ulanet et al. published in PNAS in the prototypical IGF-II-driven RIP1-Tag2 mouse model of multistage carcinogenesis demonstrate, in vivo, a role of IR in tumor progression and, importantly, in eliciting intrinsic resistance to IGF-1R targeting therapy. The researchers assessed the potential therapeutic efficacy of the IGF1R-specific monoclonal antibody A12 in these mice. Surprisingly, A12 had no significant impact on PNET growth or invasiveness, despite successfully reducing IGF1R levels. The researchers found that INSR isoforms, Insra and Insrb, as well as Igf1r, are expressed during PNET development. Moreover, IGF1R and INSR are post-transcriptionally upregulated, and IGF2 stimulation of tumor-derived β-cells resulted in the activation of both receptors. Targeted deletion of Insr in β-cells (β-IRKO) of RIP1-Tag2 mice led to decreased tumor burden and increased apoptosis. The workers also assessed the therapeutic efficacy of A12 and found that A12-treated RIP1-Tag2; β-IRKO mice showed significant inhibition of tumor growth, indicating that the loss of INSR can sensitize these tumors to anti-IGF1R therapy. Extending their findings from the PNET mouse model to human cancer, the researchers found that the INSR loss may similarly sensitize breast cancer cells to the inhibitory effects of A12. Cell lines with a high INSR/IGF1R ratio, such as MDA-MB-231, were insensitive to inhibition of IGF signaling by A12, in contrast to cell lines with a low ratio, such as MCF-7. Knocking down INSR expression by small interfering RNA sensitized both MCF-7 and the previously resistant MDA-MB-231 cells to A12 inhibition. These results suggest a functional role of INSR in tumor progression, and implicate increased INSR signaling in intrinsic resistance to anti-IGF1R therapy in an IGF2-driven PNET model.

Source: PNAS

Regression of CRPC by a Small-molecule Inhibitor of Androgen Receptor

Androgen ablation therapy causes a temporary reduction in prostate cancer tumor burden. Unfortunately, prostate cancer will begin to grow again in the absence of androgens to form castrate-recurrent disease (CRPC) and most patients succumb within 2 years. CRPC is believed to emerge after genetic and/or epigenetic changes in prostate cancer cells that render them insensitive to ADT. CRPC is characterized partly by overexpression of AR. In addition, the use of antiandrogens that target the ligand binding domain (LBD) can lead to the selection of prostate cancer cells that harbor AR mutations in the LBD.

Androgen receptor (AR) is a transcription factor and the AF region in the amino-terminal domain (NTD) of AR contains most, if not all, of the transcriptional activity. Andersen et al. in Cancer Cell recently reported a small molecule EPI-001 that interacts with and blocks transactivation of the androgen receptor amino-terminal domain. EP-001 is a BADGE (bisphenol A diglycidic ether) analog, which is specific for inhibition of AR without attenuating transcriptional activities of related steroid receptors. Unlike antiandrogens that target the C-terminal LBD and fail presumably due to gain-of-function mutations in the LBD, or expression of constitutively active splice variants, EPI-001 interacted with the AF-1 region. It inhibited protein-protein interactions with AR, and reduced AR interaction with androgen-response elements on target genes. The workers also showed that EPI-001 can block transactivation of a constitutively active AR deletion mutant containing the NTD, DNA-binding domain, and hinge region, but not the LBD. Importantly, EPI-001 blocked androgen-induced proliferation and caused cytoreduction of CRPC in xenografts dependent on AR for growth and survival without causing toxicity. Currently, there are no curative treatment options for CRPC and this agent can overcome the shortcomings of clinically used antiandrogens. The findings of this study suggest that the AR NTD is a promising target to develop therapeutics for the treatment of CRPC.

Source: Cancer Cell

Integrative Genomic and Proteomic Analyses Identify Targets for Lkb1-deficient Metastatic Lung Tumors

Genetic analyses and gene expression profiling of primary human lung tumors have identified several aberrant signaling pathways involved in the initiation of non-small cell lung cancer (NSCLC). Although large-scale genomic analyses of NSCLC have yielded a better understanding of lung cancer genetic alterations, studies defining the pathways deregulated in tumor progression and metastases are limited.

In a recent study published in Cancer Cell, Carretero et al. showed that in mice, Lkb1 deletion and activation of KrasG12D resulted in lung tumors with a high penetrance of lymph node and distant metastases. They analyzed these primary and metastatic de novo lung cancers with integrated genomic and proteomic profiles, and identified gene and phosphoprotein signatures associated with Lkb1 loss and progression to invasive and metastatic lung tumors. It was seen that Kras/Lkb1 primary and metastatic tumors have upregulated expression of markers and inducers of EMT. Furthermore, they determined that two key modulators of focal adhesion dynamics, SRC and FAK, are upregulated by Lkb1 loss during NSCLC progression. Similarly, LKB1 loss in vitro also resulted in SRC activation, increased motility, and SRC-dependent adhesion. In fact, migration was selectively abrogated by SRC and FAK inhibition in LKB1-deficient cells. Finally, whereas Kras mutant lung tumors were sensitive to the combined inhibition of the PI3K and MEK pathways, the workers found that Kras/Lkb1 tumors were resistant to these inhibitors, and that sensitivity could be restored by additional targeting of SRC. It is also important to note that the addition of Dasatinib to combined PI3K/MEK inhibition induced tumor shrinkage in LKB1-deficient tumors, revealing an important role of SFKs in tumor growth and promoting resistance to combined PI3K/MEK inhibition. It was somewhat surprising that single-agent Dasatinib led to increased volume of Kras/Lkb1 tumors and persisting Akt and EMT signatures. Lastly, Kras/Lkb1 mice treated with Dasatinib alone did not show any evidence of metastasis, further reinforcing the data that the Src family members are important mediators of metastatic progression in Kras/Lkb1-driven lung cancer. In conclusion, these results imply that despite the complex transcriptional and signaling changes that occur in the setting of LKB1 loss and progression of NSCLC, these tumors may still be addicted to isolated oncogenic events that can be successfully therapeutically targeted. These studies also demonstrate that integrated genomic and proteomic analyses can be used to identify signaling pathways that may be targeted for treatment.

Source: Cancer Cell

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