Frequent 4EBP1 Amplification Induces Synthetic Dependence on FGFR Signaling in Cancer

Simple Summary Our work establishes that amplification of 4EBP1, as a part of Chr. 8p11, creates a synthetic dependency on FGFR1 signaling in cancer. 4EBP1 is phosphorylated by FGFR1 and PI3K signaling, and accordingly cancer with 4EBP1-FGFR1 amplification is more sensitive to FGFR1 and PI3K inhibition due to inhibition of 4EBP1 phosphorylation. Moreover, we characterize the translational targets of 4EBP1 and identify that 4EBP1 specifically regulates the translation of genes involved in insulin signaling, glucose metabolism, and the inositol pathway that plays a role in cancer progression. The eIF4E translation initiation factor has oncogenic properties and concordantly, the inhibitory eIF4E-binding protein (4EBP1) is considered a tumor suppressor. The exact molecular effects of 4EBP1 activation in cancer are still unknown. Surprisingly, 4EBP1 is a target of genomic copy number gains (Chr. 8p11) in breast and lung cancer. We noticed that 4EBP1 gains are genetically linked to gains in neighboring genes, including WHSC1L1 and FGFR1. Our results show that FGFR1 gains act to attenuate the function of 4EBP1 via PI3K-mediated phosphorylation at Thr37/46, Ser65, and Thr70 sites. This implies that not 4EBP1 but instead FGFR1 is the genetic target of Chr. 8p11 gains in breast and lung cancer. Accordingly, these tumors show increased sensitivity to FGFR1 and PI3K inhibition, and this is a therapeutic vulnerability through restoring the tumor-suppressive function of 4EBP1. Ribosome profiling reveals genes involved in insulin signaling, glucose metabolism, and the inositol pathway to be the relevant translational targets of 4EBP1. These mRNAs are among the top 200 translation targets and are highly enriched for structure and sequence motifs in their 5 ' UTR, which depends on the 4EBP1-EIF4E activity. In summary, we identified the translational targets of 4EBP1-EIF4E that facilitate the tumor suppressor function of 4EBP1 in cancer

Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma

PIM kinase expression in human lymphomas can influence the outcome of chemotherapy, and blocking cap-dependent translation can reverse PIM-mediated rapamycin resistance in murine lymphomas

The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma

Insights into cancer genetics can lead to therapeutic opportunities. By cross-referencing chromosomal changes with an unbiased genetic screen we identify the ephrin receptor A7 (EPHA7) as a tumor suppressor in follicular lymphoma (FL). EPHA7 is a target of 6q deletions and inactivated in 72% of FLs. Knockdown of EPHA7 drives lymphoma development in a murine FL model. In analogy to its physiological function in brain development, a soluble splice variant of EPHA7 (EPHA7(TR)) interferes with another Eph-receptor and blocks oncogenic signals in lymphoma cells. Consistent with this drug-like activity, administration of the purified EPHA7(TR) protein produces antitumor effects against xenografted human lymphomas. Further, by fusing EPHA7(TR) to the anti-CD20 antibody (rituximab) we can directly target this tumor suppressor to lymphomas in vivo. Our study attests to the power of combining descriptive tumor genomics with functional screens and reveals EPHA7(TR) as tumor suppressor with immediate therapeutic potential

Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy.

Loss of cell cycle controls is a hallmark of cancer and has a well-established role in aggressive B cell malignancies. However, the role of such lesions in indolent follicular lymphoma (FL) is unclear and individual lesions have been observed with low frequency. By analyzing genomic data from two large cohorts of indolent FLs, we identify a pattern of mutually exclusive (P = 0.003) genomic lesions that impair the retinoblastoma (RB) pathway in nearly 50% of FLs. These alterations include homozygous and heterozygous deletions of the p16/CDKN2a/b (7%) and RB1 (12%) loci, and more frequent gains of chromosome 12 that include CDK4 (29%). These aberrations are associated with high-risk disease by the FL prognostic index (FLIPI), and studies in a murine FL model confirm their pathogenic role in indolent FL. Increased CDK4 kinase activity toward RB1 is readily measured in tumor samples and indicates an opportunity for CDK4 inhibition. We find that dual CDK4 and BCL2 inhibitor treatment is safe and effective against available models of FL. In summary, frequent RB pathway lesions in indolent, high-risk FLs indicate an untapped therapeutic opportunity

Genomic studies indicate a novel combination therapy for follicular lymphoma

Follicular lymphoma (FL) is an incurable form of B-cell lymphoma. Genomic alterations that inactivate RB signaling are surprisingly common in indolent FL. We show that FLs that are positive for phosphorylated RB respond to dual CDK4/BCL2 inhibition. Our results imply that RB phosphorylation identifies patients likely to benefit from such dual intervention

Functional genomics lead to new therapies in follicular lymphoma

Recent technological advances allow analysis of genomic changes in cancer in unprecedented detail. The next challenge is to prioritize the multitude of genetic aberrations found and identify therapeutic opportunities. We recently completed a study that illustrates the use of unbiased genetic screens and murine cancer models to find therapeutic targets among complex genomic data. We genetically dissected the common deletion of chromosome 6q and identified the ephrin receptor A7 (EPHA7) as a tumor suppressor in lymphoma. Notably, EPHA7 encodes a soluble splice variant that acts as an extrinsic tumor suppressor. Accordingly, we developed an antibody-based strategy to specifically deliver EPHA7 back to tumors that have lost this gene. Recent sequencing studies have implicated EPHA7 in lung cancer and other tumors, suggesting a broader therapeutic potential for antibody-mediated delivery of this tumor suppressor for cancer therapy. Together, our comprehensive approach provides new insights into cancer biology and may directly lead to the development of new cancer therapies

Oncogenic Pim Kinase Activity Provides Resistance to Mtor Inhibition in Vitro and In Vivo

Abstract Abstract 3974 Poster Board III-910 The PI3K/Akt/mTor pathway is among the most frequently deregulated in human cancers, including many leukemias and lymphomas, and inhibitors targeting it at multiple levels are either clinically available or under development. The Pim family proteins are oncogenic serine/threonine kinases expressed in many malignancies and that have numerous overlapping downstream targets and functional consequences with PI3K/Akt/mTor. We here investigate the role of Pim proteins in oncogenesis and their ability in particular to mediate resistance to mTor inhibition. We find over-expression and genomic amplification of Pim1 and Pim2 in tumor samples and cell lines derived from patients with multiple B lymphomas. We show that both Pim1 and Pim2 powerfully mediate resistance to apoptosis in the murine pro-B cell line FL5-12 when withdrawn from IL-3. In murine tumor cells with constitutive activation of mTor, Pim1 and Pim2 provide resistance to treatment with the mTor inhibitor rapamycin. In vivo, we find that murine Pim2 (mPim2) accelerates tumorigenesis in the Eu-Myc transgenic model of Burkitt's lymphoma in a manner highly similar to Akt. However, unlike Akt, mPim2 leads to tumors that resist sensitization to chemotherapy by co-administration of rapamycin. We also investigate Pim1's role as a target of aberrant somatic hypermutation (ASHM), the process by which the enzyme activation induced deamidase (AID) introduces mutations into the coding and non-coding regions of the Pim1 locus and other proto-oncogenes in many B-cell malignancies. We find that structural Pim1 mutants found in patient tumors samples retain their ability to accelerate tumorigenesis in the Eu-Myc model in vivo and to mediate resistance to apoptosis and rapamycin in vitro. In conclusion, Pim activity is clinically significant, highly oncogenic, and provides resistance to mTor inhibition. Pim inhibition is therefore an attractive therapeutic approach, especially in combination with PI3K/Akt/mTor inhibition, even as ASHM provides a potential mechanism for B-cell tumors to escape it. Disclosures: No relevant conflicts of interest to declare

Targeted cancer therapy What if the driver is just a messenger?

“Shoot the driver” is the paradigm of targeted cancer therapy. However, resistance to targeted inhibitors of signaling pathways is a major problem. In part, the redundancy of signaling networks can bypass targeted inhibitors and thereby reduce their biological effect. In this case, the driver turns out to be one of several potential messengers and is easily replaced. Cocktails of multiple targeted inhibitors are an obvious solution. This is limited, however, by the lack of potent inhibitors and may also produce increased toxicity. Therefore, we explored the direct blockade of a key biological activity downstream from multiple converging oncogenic signals. Specifically, several oncogenic signaling pathways, including AKT, MAPK and PIM kinase signals, converge on the activation of cap-dependent translation. In cancer cells, aberrant activation of cap-dependent translation favors the increased expression of short-lived oncoproteins like c-MYC, MCL1, CYCLIND1 and the PIM kinases. Intriguingly, cancer cells are especially sensitive to even temporary reductions in these proteins. We will discuss our findings concerning translational inhibitor therapy in cancer