Phosphorylation by Cdk2 is Required for Myc to Repress Ras-induced Senescence

It has been known for over two decades that no more than two activated oncogenes, c-myc and H-ras, are sufficient to transform primary rodent cells into cancerous cells. KRas and Myc promote growth, but their expression can also induce apoptosis or cellular senescence. A recent paper by Hydbring et al. in PNAS provides a rationale for the cooperativity between Myc and Ras in malignant transformation. Their results suggest that Myc and Ras complement each other by repressing senescence and apoptosis, respectively, not necessary attributable to abnormal functions of these proteins. They present evidence for an important function of Myc in repressing Ras-induced senescence as well as senescence triggered by other activators of the MAPK pathway, including activated c-Raf, Mek, and TPA. Cyclin-dependent kinase 2 (Cdk2) suppresses the induction of senescence by Myc and phosphorylates Myc to bypass Ras-induced senescence, confirming its importance in averting oncogene-induced senescence. Over-expression of Myc can circumvent the induction of senescence by oncogenic Ras, and this activity is dependent on Cdk2-mediated phosphorylation of Myc at Ser-62. Furthermore, inhibition of Cdk2 following the activation of oncogenic Ras blocks Myc-mediated inhibition of senescence and attenuates the accumulation of activating and repressive MYC-containing complexes at anti-senescence and pro-senescence gene promoters, respectively.

Therefore, the results of this study indicate that Cdk2 should be re-evaluated as a target for cancer therapy. Cdk2-selective pharmacological inhibitors push Myc-transformed cells into senescence, suggesting that the inhibition of Cdk2, possibly in combination with Cdk1 inhibition, could potentially be a therapeutical principle for combating tumors with deregulated Myc or Ras. This emphasizes the urge to find drugs that can target Myc and/or Ras activity, but cooperativity between Myc and Ras remains unclear.

Source: PNAS

 

Preexistence and Clonal Selection of MET Amplification in EGFR Mutant NSCLC

Kinase inhibitors have emerged as effective clinical therapies for cancers that exhibit oncogene addiction to a particular kinase. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are effective clinical therapies for patients with advanced non-small cell lung cancer (NSCLC) who have EGFR-activating mutations. A recent study by Turke et al. published in Cancer Cell modeled in vitro resistance to PF00299804, an irreversible EGFR inhibitor, in the TKI-sensitive EGFR-mutant NSCLC cell line, HCC827. Researchers evaluated the potency of the MET ligand, HGF, to promote resistance to EGFR TKIs. They observed that MET amplification is present in a small fraction of cells before drug exposure, and its development is dramatically accelerated by HGF. MET amplification activates ERBB3/PI3K/AKT signaling in EGFR-mutant lung cancers and causes resistance to EGFR kinase inhibitors. MET activation also induces drug resistance, but through GAB1 signaling. This activation of MET signaling (by amplification and HGF mediation) may, in fact, account for a larger fraction of gefitinib- or erlotinib-resistant tumors. The workers identified subpopulations of cells with MET amplification prior to drug exposure. Surprisingly, HGF accelerated the development of MET amplification both in vitro and in vivo. EGFR kinase inhibitor resistance either due to MET amplification or autocrine HGF production was cured in vivo by combined EGFR and MET inhibition.

These findings provide insight into the origin of drug resistance in EGFR-mutant cancers and into the future therapeutic strategies for the treatment of EGFR-mutant NSCLC. The results support the rationale for a combination of an irreversible EGFR inhibitor (effective against EGFR T790M) and a MET inhibitor as initial therapy, specifically in a molecularly defined cohort of patients with evidence of preexisting MET amplification. There is also potential to prospectively identify treatment-naive patients with EGFR-mutant lung cancer who are likely to develop MET amplification and may benefit from such initial combination therapy.

Source: Cancer Cell

 

Chemical Proteomics Native Target Profiling of INNO-406 in CML Cells

Expression of the oncogenic fusion protein BCR-ABL is the hallmark of chronic myeloid leukemia (CML) and inhibition of its tyrosine kinase activity by imatinib has become the paradigm of targeted therapy. The newest of these drugs, the dual ABL/LYN inhibitor INNO-406 (NS-187, bafetinib), is a structural analog of imatinib and nilotinib, which exhibits a 25- to 55-fold increase over imatinib in in vitro activity against BCR-ABL. Rix et al. in Leukemia developed an unbiased chemical proteomics native target profile of INNO-406 in CML cells combined with functional assays using 272 recombinant kinases. By applying a two-tiered approach, they described the global target profile of INNO-406, which, together with the profiles of imatinib, nilotinib, dasatinib, and bosutinib, provides a basis for patient-specific use of such kinase inhibitors as single agents or in combination therapy against CML. The workers identified several new INNO-406 targets, including the kinases ZAK, DDR1/2, and various ephrin receptors. They also observed potent activity against PDGFRa V561D, but not the D842V mutant, both of which are frequently found in GIST. The oxidoreductase NQO2, inhibited by both imatinib and nilotinib, is not a relevant target of INNO-406.

Overall, INNO-406 has an improved activity over imatinib, but has a slightly broader target profile than that of imatinib and nilotinib. However, one of the most relevant differences of INNO-406 from other second generation BCR-ABL inhibitors lies in its distinct selectivity profile about the SFK and TEC family kinases, while retaining improved efficacy against imatinib-resistant CML cells through the inhibition of LYN. In contrast to dasatinib and bosutinib, INNO-406 does not inhibit all SRC kinases and most TEC family kinases and is therefore expected to elicit fewer immune-related side effects. Thus, given the improved efficacy against imatinib-resistant CML cells through its potent inhibition of LYN in addition to wild-type BCR-ABL and most of its clinically relevant mutants, INNO-406 represents an attractive additional component in the drug arsenal against CML.

Source: Leukemia

 

Mutant p53 Drives Invasion by Promoting Integrin Recycling

p53 is a tumor suppressor protein whose function is frequently lost in cancers through missense mutations within the TP53 gene. This results in the expression of point-mutated p53 proteins that have both lost wild-type tumor suppressor activity and show gain of functions that contribute to transformation and metastasis. Muller et al. identified a key mechanism by which mutant p53 can promote invasive behavior of cells through a gain of function that contribute to transformation and metastasis. These activities of p53 reflect enhanced integrin and epidermal growth factor receptor (EGFR) trafficking, which depends on Rab-coupling protein (RCP).  

The results published in Cell showed that the ability of mutant p53 proteins to contribute to the development of invasive and metastatic cancers in vivo was paralleled by their ability to enhance RCP-dependent recycling of integrin in H1299 lung cancer cells, thereby promoting trafficking and signaling of growth factor receptors. Mutant p53 was found to reflect an inhibition of TAp63, as illustrated by MCF 10A cells that exhibited enhanced cell invasion and transformation. These findings can drive both random migration and invasion through the enhancement of integrin recycling pathways. This new appreciation of mutant p53 function raises the possibility of the mutant protein being a target for the design of novel therapies aimed at inhibiting cancer dissemination, rather than the appearance of the primary tumor. These findings indicate a possibility that blocking alpha5/beta1-integrin and/or the EGF receptor will have therapeutic benefits in mutant p53-expressing cancers.

Source: Cell

 

 

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