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The selective allosteric ABL1 inhibitor ABL001 (asciminib) represents a new inhibitory mechanism for BCR–ABL1-driven malignancies, and its efficacy and evolving mechanisms of resistance do not overlap with those of other BCR–ABL1 kinase inhibitors. Dual targeting of gene fusion Current inhibitors targeting the BCR–ABL1 mutation have saved many lives but their application is limited by resistance-driving mutations. Here, the authors report the characterization of ABL001, a new allosteric ABL inhibitor. The compound represents a new inhibitory enzymatic mechanism for BCR–ABL-driven malignancies and could be applied for cases of resistance. The authors note that its efficacy and evolving mechanisms of resistance do not overlap with other BCR–ABL kinase inhibitors. Chronic myeloid leukaemia (CML) is driven by the activity of the BCR–ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of patients treated with imatinib surviving for more than 10 years 1 . Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML 2 . Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR–ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment 3 , 4 . Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph + ) acute lymphoblastic leukaemia. In contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation. ABL001 and second-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations, with genetic barcoding studies revealing pre-existing clonal populations with no shared resistance between ABL001 and the catalytic inhibitor nilotinib. Consistent with this profile, acquired resistance was observed with single-agent therapy in mice; however, the combination of ABL001 and nilotinib led to complete disease control and eradicated CML xenograft tumours without recurrence after the cessation of treatment.

Deregulation of the PI3K signaling pathway is observed in many human cancers and occurs most frequently through loss of PTEN phosphatase tumor suppressor function or through somatic activating mutations in the Class IA PI3K, PIK3CA. Tumors harboring activated p110α, the protein product of PIK3CA, require p110α activity for growth and survival and hence are expected to be responsive to inhibitors of its lipid kinase activity. Whether PTEN-deficient cancers similarly depend on p110α activity to sustain activation of the PI3K pathway has been unclear. In this study, we used a single-vector lentiviral inducible shRNA system to selectively inactivate the three Class IA PI3Ks, PIK3CA, PIK3CB, and PIK3CD, to determine which PI3K isoforms are responsible for driving the abnormal proliferation of PTEN-deficient cancers. Down-regulation of PIK3CA in colorectal cancer cells harboring mutations in PIK3CA inhibited downstream PI3K signaling and cell growth. Surprisingly, PIK3CA depletion affected neither PI3K signaling nor cell growth in 3 PTEN-deficient cancer cell lines. In contrast, down-regulation of the PIK3CB isoform, which encodes p110β, resulted in pathway inactivation and subsequent inhibition of growth in both cell-based and in vivo settings. This essential function of PIK3CB in PTEN-deficient cancer cells required its lipid kinase activity. Our findings demonstrate that although p110α activation is required to sustain the proliferation of established PIK3CA-mutant tumors, PTEN-deficient tumors are dependent instead on p110β signaling. This unexpected finding demonstrates the need to tailor therapeutic approaches to the genetic basis of PI3K pathway activation to achieve optimal treatment response.

Persistent expression of certain oncogenes is required for tumor maintenance. This phenotype is referred to as oncogene addiction and has been clinically validated by anticancer therapies that specifically inhibit oncoproteins such as BCR-ABL, c-Kit, HER2, PDGFR, and EGFR. Identifying additional genes that are required for tumor maintenance may lead to new targets for anticancer drugs. Although the role of aberrant Wnt pathway activation in the initiation of colorectal cancer has been clearly established, it remains unclear whether sustained Wnt pathway activation is required for colorectal tumor maintenance. To address this question, we used inducible β-catenin shRNAs to temporally control Wnt pathway activation in vivo. Here, we show that active Wnt/β-catenin signaling is required for maintenance of colorectal tumor xenografts harboring APC mutations. Reduced tumor growth upon β-catenin inhibition was due to cell cycle arrest and differentiation. Upon reactivation of the Wnt/β-catenin pathway colorectal cancer cells resumed proliferation and reacquired a crypt progenitor phenotype. In human colonic adenocarcinomas, high levels of nuclear β-catenin correlated with crypt progenitor but not differentiation markers, suggesting that the Wnt/β-catenin pathway may also control colorectal tumor cell fate during the maintenance phase of tumors in patients. These results support efforts to treat human colorectal cancer by pharmacological inhibition of the Wnt/β-catenin pathway.

The authors implement a collection of patient-derived xenograft tumors to test cancer drug responses. Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.

A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-κΒ pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types. Cancer genomics refined Two Articles in this issue add major data sets to the growing picture of the cancer genome. Bignell et al . analysed a large number of homozygous gene deletions in a collection of 746 publicly available cancer cell lines. Combined with information about hemizygous deletions of the same genes, the data suggest that many deletions found in cancer reflect the position of a gene at a fragile site in the genome, rather than as a recessive cancer gene whose loss confers a selective growth advantage. Beroukhim et al . present the largest data set to date on somatic copy-number variations across more than 3,000 specimens of human primary cancers. Many alterations are shared between multiple tumour types. Functional experiments demonstrate an oncogenic role for the apoptosis genes MCL1 and BCL2L1 that are associated with amplifications found in many cancers. One way of discovering genes with key roles in cancer development is to identify genomic regions that are frequently altered in human cancers. Here, high-resolution analyses of somatic copy-number alterations (SCNAs) in numerous cancer specimens provide an overview of regions of focal SCNA that are altered at significant frequency across several cancer types. An oncogenic function is also found for the anti-apoptosis genes MCL1 and BCL2L1 , which reside in amplified genome regions in many cancers.

Medical guidelines for interferon-alpha2a or -alpha2b (IFN-alpha) treatment of chronic hepatitis C virus (HCV) infection depend upon baseline liver histology. A better long-term response to IFN-alpha therapy correlates with less inflammation and absence of cirrhosis. It has been suggested that the presence of cirrhosis in patients with chronic hepatitis C virus infection may be predicted based on an AST/ALT ratio > or = 1. This study was designed to determine if the presence of cirrhosis can be predicted in patients with chronic HCV infection by such a ratio. Seventy-seven patients, including 23 cirrhotics, with chronic HCV infection were studied. Serum ALT, AST, and HCV-RNA levels and hepatic activity index (HAI), reflecting histologic inflammation in all liver biopsies, were assessed. AST/ALT ratios and mean ALT, AST, and HCV-RNA were determined for both cirrhotic and noncirrhotic patients. HAI was correlated with ALT, AST, and HCV-RNA levels, the latter determined by quantitative RT-PCR. The likelihood ratio (LR) and positive predictive value of an AST/ALT ratio > or = 1 for cirrhosis was 7.3 and only 77%, respectively. In cirrhotics vs noncirrhotics, there were no significant differences between mean serum ALT (149 +/- 28 vs 176 +/- 17 units/liter), AST (139 +/- 28 vs 102 +/- 8 units/liter), or HCV-RNA levels (589,160 +/- 147,053 vs 543,915 +/- 75,497 copies/ml), respectively. There was a significant, but clinically weak, correlation between serum ALT and HAI (r = 0.234), and none between HAI and either serum AST or HCV-RNA levels. Our results support the need for a liver biopsy prior to treatment of chronic HCV infection, since the AST/ALT ratio fails to predict accurately the presence of cirrhosis.

• Objectives To describe quality-of-life outcomes; determine relationships between quality of life and demographic, physical, psychosocial, and clinical variables; and identify predictors of quality of life at 1 month after implantation of a left ventricular assist device. • Methods Patients who received either an implantable pneumatic (n = 38) or a vented electric (n = 54) left ventricular assist device as a bridge to heart transplantation between August 1, 1994, and August 31, 1999, completed 6 instruments used to measure quality of life and factors related to quality of life. Data were analyzed by using descriptive statistics, Pearson correlations, Mann-Whitney U tests, and forward, stepwise multiple regression. • Results Overall satisfaction with quality of life was quite high as determined from the total score on the Quality of Life Index (mean = 0.69). Patients were very satisfied with the implantation and thought that they would do well after future heart transplant surgery. Patients had a moderate level of stress. Significant predictors of overall quality of life were psychological symptoms, stress, and race; these accounted for 46% of variance in quality of life. • Conclusions Patients were satisfied with their quality of life at 1 month after implantation of a left ventricular assist device. However, they were least satisfied with their health and functioning and yet were optimistic about how well they thought they would do after heart transplantation. Psychological factors were the strongest predictors of satisfaction with overall quality of life.

Persistent expression of certain oncogenes is required for tumor maintenance. This phenotype is referred to as oncogene addiction and has been clinically validated by anticancer therapies that specifically inhibit oncoproteins such as BCR-ABL, c-Kit, HER2, PDGFR, and EGFR. Identifying additional genes that are required for tumor maintenance may lead to new targets for anticancer drugs. Although the role of aberrant Wnt pathway activation in the initiation of colorectal cancer has been clearly established, it remains unclear whether sustained Wnt pathway activation is required for colorectal tumor maintenance. To address this question, we used inducible β-catenin shRNAs to temporally control Wnt pathway activation in vivo. Here, we show that active Wnt/β-catenin signaling is required for maintenance of colorectal tumor xenografts harboring APC mutations. Reduced tumor growth upon β-catenin inhibition was due to cell cycle arrest and differentiation. Upon reactivation of the Wnt/β-catenin pathway colorectal cancer cells resumed proliferation and reacquired a crypt progenitor phenotype. In human colonic adenocarcinomas, high levels of nuclear β-catenin correlated with crypt progenitor but not differentiation markers, suggesting that the Wnt/β-catenin pathway may also control colorectal tumor cell fate during the maintenance phase of tumors in patients. These results support efforts to treat human colorectal cancer by pharmacological inhibition of the Wnt/β-catenin pathway. [PUBLICATION ABSTRACT]

Deregulation of the PI3K signaling pathway is observed in many human cancers and occurs most frequently through loss of PTEN phosphatase tumor suppressor function or through somatic activating mutations in the Class IA PI3K, PIK3CA. Tumors harboring activated p110α, the protein product of PIK3CA, require p110α activity for growth and survival and hence are expected to be responsive to inhibitors of its lipid kinase activity. Whether PTEN-deficient cancers similarly depend on p110α activity to sustain activation of the PI3K pathway has been unclear. In this study, we used a single-vector lentiviral inducible shRNA system to selectively inactivate the three Class IA PI3Ks, PIK3CA, PIK3CB, and PIK3CD, to determine which PI3K isoforms are responsible for driving the abnormal proliferation of PTEN-deficient cancers. Down-regulation of PIK3CA in colorectal cancer cells harboring mutations in PIK3CA inhibited downstream PI3K signaling and cell growth. Surprisingly, PIK3CA depletion affected neither PI3K signaling nor cell growth in 3 PTEN-deficient cancer cell lines. In contrast, down-regulation of the PIK3CB isoform, which encodes p110β, resulted in pathway inactivation and subsequent inhibition of growth in both cell-based and in vivo settings. This essential function of PIK3CB in PTEN-deficient cancer cells required its lipid kinase activity. Our findings demonstrate that although p110α activation is required to sustain the proliferation of established PIK3CA-mutant tumors, PTEN-deficient tumors are dependent instead on p110β signaling. This unexpected finding demonstrates the need to tailor therapeutic approaches to the genetic basis of PI3K pathway activation to achieve optimal treatment response. [PUBLICATION ABSTRACT]