AKT- a key molecular regulator of PI-3K signaling pathway, is somatically mutated in diverse solid cancer types, and aberrant AKT activation promotes altered cancer cell growth, survival, and ...metabolism
. The most common of AKT mutations (AKT1 E17K) sensitizes affected solid tumors to AKT inhibitor therapy
. However, the pathway dependence and inhibitor sensitivity of the long tail of potentially activating mutations in AKT is poorly understood, limiting our ability to act clinically in prospectively characterized cancer patients. Here we show, through population-scale driver mutation discovery combined with functional, biological, and therapeutic studies that some but not all missense mutations activate downstream AKT effector pathways in a growth factor-independent manner and sensitize tumor cells to diverse AKT inhibitors. A distinct class of small in-frame duplications paralogous across AKT isoforms induce structural changes different than those of activating missense mutations, leading to a greater degree of membrane affinity, AKT activation, and cell proliferation as well as pathway dependence and hyper-sensitivity to ATP-competitive, but not allosteric AKT inhibitors. Assessing these mutations clinically, we conducted a phase II clinical trial testing the AKT inhibitor capivasertib (AZD5363) in patients with solid tumors harboring AKT alterations (NCT03310541). Twelve patients were enrolled, out of which six harbored AKT1-3 non-E17K mutations. The median progression free survival (PFS) of capivasertib therapy was 84 days (95% CI 50-not reached) with an objective response rate of 25% (n = 3 of 12) and clinical benefit rate of 42% (n = 5 of 12). Collectively, our data indicate that the degree and mechanism of activation of oncogenic AKT mutants vary, thereby dictating allele-specific pharmacological sensitivities to AKT inhibition.
Tumor suppressor PAR-4 acts in part by modulating sensitivity to apoptosis, but the basis for its activity is not fully understood. In this study, we describe a novel mechanism of antiapoptosis by ...NF-κB, revealing that it can block PAR-4-mediated apoptosis by downregulating trafficking of the PAR-4 receptor GRP78 from the endoplasmic reticulum to the cell surface. Mechanistic investigations revealed that NF-κB mediated this antiapoptotic mechanism by upregulating expression of UACA, a proinflammatory protein in certain disease settings. In clinical specimens of cancer, a strong correlation existed between NF-κB activity and UACA expression, relative to normal tissues. UACA bound to intracellular PAR-4 in diverse cancer cells, where it prevented translocation of GRP78 from the endoplasmic reticulum to the cell surface. This pathway of antiapoptosis could be inhibited by suppressing levels of NF-κB or UACA expression, which enhanced endoplasmic reticulum stress and restored GRP78 trafficking to the cell surface, thereby sensitizing cancer cells to apoptosis by extracellular PAR-4 or GRP78 agonistic antibody. In summary, our results identify a novel intracellular pathway of apoptosis mediated by NF-κB through UACA elevation, which by attenuating endoplasmic reticulum stress and GRP78 translocation to the cell surface can blunt the sensitivity of cancer cells to apoptosis.
Most mutations in cancer are rare, which complicates the identification of therapeutically significant mutations and thus limits the clinical impact of genomic profiling in patients with cancer. ...Here, we analyzed 24,592 cancers including 10,336 prospectively sequenced patients with advanced disease to identify mutant residues arising more frequently than expected in the absence of selection. We identified 1,165 statistically significant hotspot mutations of which 80% arose in 1 in 1,000 or fewer patients. Of 55 recurrent in-frame indels, we validated that novel
duplications induced pathway hyperactivation and conferred AKT inhibitor sensitivity. Cancer genes exhibit different rates of hotspot discovery with increasing sample size, with few approaching saturation. Consequently, 26% of all hotspots in therapeutically actionable oncogenes were novel. Upon matching a subset of affected patients directly to molecularly targeted therapy, we observed radiographic and clinical responses. Population-scale mutant allele discovery illustrates how the identification of driver mutations in cancer is far from complete.
Our systematic computational, experimental, and clinical analysis of hotspot mutations in approximately 25,000 human cancers demonstrates that the long right tail of biologically and therapeutically significant mutant alleles is still incompletely characterized. Sharing prospective genomic data will accelerate hotspot identification, thereby expanding the reach of precision oncology in patients with cancer.
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Mutational activation of the PI3K/AKT pathway is among the most common pro-oncogenic events in human cancers. The clinical utility of PI3K and AKT inhibitors has, however, been modest to date. Here, ...we used CRISPR-mediated gene editing to study the biological consequences of AKT1 E17K mutation by developing an AKT1 E17K-mutant isogenic system in a
-null background. AKT1 E17K expression under the control of its endogenous promoter enhanced cell growth and colony formation, but had a paradoxical inhibitory effect on cell migration and invasion. The mechanistic basis by which activated AKT1 inhibited cell migration and invasion was increased E-cadherin expression mediated by suppression of
transcription via altered β-catenin subcellular localization. This phenotypic effect was AKT1-specific, as AKT2 activation had the opposite effect, a reduction in E-cadherin expression. Consistent with the opposing effects of AKT1 and AKT2 activation on E-cadherin expression, a pro-migratory effect of AKT1 activation was not observed in breast cancer cells with PTEN loss or expression of an activating
mutation, alterations which induce the activation of both AKT isoforms. The results suggest that the use of AKT inhibitors in patients with breast cancer could paradoxically accelerate metastatic progression in some genetic contexts and may explain the frequent coselection for
mutations in
-mutated breast tumors. IMPLICATIONS: AKT1 E17K mutation in breast cancer impairs migration/invasiveness via sequestration of β-catenin to the cell membrane leading to decreased
transcription, resulting in increased E-cadherin expression and a reversal of epithelial-mesenchymal transition.
Prostate apoptosis response-4 (Par-4) is a tumor suppressor that induces apoptosis in cancer cells. However, the physiological function of Par-4 remains unknown. Here we show that conventional Par-4 ...knockout (Par-4
) mice and adipocyte-specific Par-4 knockout (AKO) mice, but not hepatocyte-specific Par-4 knockout mice, are obese with standard chow diet. Par-4
and AKO mice exhibit increased absorption and storage of fat in adipocytes. Mechanistically, Par-4 loss is associated with
downregulation and activation of p53. We identified complement factor
as a p53-regulated gene linked to fat storage in adipocytes.
re-expression in adipocytes or
deletion reversed the obese mouse phenotype. Moreover, obese human subjects showed lower expression of Par-4 relative to lean subjects, and in longitudinal studies, low baseline Par-4 levels denoted an increased risk of developing obesity later in life. These findings indicate that Par-4 suppresses p53 and its target
to regulate obesity.
The guardian of the genome, p53, is often mutated in cancer and may contribute to therapeutic resistance. Given that p53 is intact and functional in normal tissues, we harnessed its potential to ...inhibit the growth of p53-deficient cancer cells. Specific activation of p53 in normal fibroblasts selectively induced apoptosis in p53-deficient cancer cells. This paracrine effect was mediated by p53-dependent secretion of the tumor suppressor Par-4. Accordingly, the activation of p53 in normal mice, but not p53−/− or Par-4−/− mice, caused systemic elevation of Par-4, which induced apoptosis of p53-deficient tumor cells. Mechanistically, p53 induced Par-4 secretion by suppressing the expression of its binding partner, UACA, which sequesters Par-4. Thus, normal cells can be empowered by p53 activation to induce Par-4 secretion for the inhibition of therapy-resistant tumors.
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•Activation of p53 function in normal cells for paracrine apoptosis of cancer cells•p53 recruits another tumor suppressor, Par-4, to execute its paracrine function•Identification of small molecules with specific targets as Par-4 secretagogues•UACA sequesters and inhibits Par-4 secretion
Loss of tumor suppressor p53 often contributes to therapy resistance in tumors. In this study, Rangnekar and colleagues activated wild-type p53 in normal cells to trigger paracrine apoptosis of p53-deficient cancer cells. This paracrine effect was mediated by the tumor suppressor Par-4, which specifically induces apoptosis in cancer cells. P53 activation suppresses UACA expression and releases Par-4 from sequestration by UACA. Thus, p53 activation or UACA inhibition may empower normal cells to inhibit p53-deficient tumors.
Selectivity toward cancer cells is the most desirable element in cancer therapeutics. Par-4 is a cancer cell-selective proapoptotic protein that functions intracellularly in the cytoplasmic and ...nuclear compartments as a tumor suppressor. Moreover, recent findings indicate that the Par-4 protein is secreted by cells, and extracellular Par-4 induces cancer cell-specific apoptosis by interaction with the cell-surface receptor GRP78. This review describes the mechanisms underlying the apoptotic effects of both extracellular and intracellular Par-4 acting through its effector domain SAC.
Par(−4)oxysm in Breast Cancer Shrestha-Bhattarai, Tripti; Hebbar, Nikhil; Rangnekar, Vivek M.
Cancer cell,
07/2013, Letnik:
24, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Women suffering from breast cancer often succumb to incurable recurrent disease resulting from therapy-resistant cancer cells. In this issue of Cancer Cell, Alvarez and colleagues identify ...downregulation of the tumor suppressor Par-4 as the key determinant in apoptosis evasion, which leads to tumor recurrence in breast cancer.
Par-4 prevents breast cancer recurrence Hebbar, Nikhil; Shrestha-Bhattarai, Tripti; Rangnekar, Vivek M
Breast cancer research : BCR,
01/2013, Letnik:
15, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Therapy resistance and disease recurrence are two of the most challenging aspects in breast cancer treatment. A recent article in Cancer Cell makes a significant contribution toward a better ...understanding of this therapeutic problem by establishing downregulation of the tumor suppressor Par-4 as the primary determinant of breast cancer recurrence. This viewpoint brings forth the importance of their findings and its implications on future research and therapy.
Tumor suppressor genes play an important role in preventing neoplastic transformation and maintaining normal tissue homeostasis. Par-4 is one such tumor suppressor which is unique in its ability to ...selectively induce apoptosis in cancer cells while leaving the normal cells unaffected. The cancer cell specific activity of Par-4 is elicited through intracellular as well as extracellular mechanisms. Intracellularly Par-4 acts through the inhibition of pro-survival pathways and activation of Fas mediated apoptosis whereas extracellular (secreted Par-4) acts by binding to cell surface GRP78 leading to activation of the extrinsic apoptotic pathway. Many studies have highlighted the importance of Par-4 not only in preventing cancer development/recurrence but also as a promising anticancer therapeutic agent.
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