Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice

Abstract

The principal reason for failure of targeted cancer therapies is the emergence of resistant clones that regenerate the tumor. Therapeutic efficacy therefore depends on not only how effectively a drug inhibits its target, but also the innate or adaptive functional redundancy of that target and its attendant pathway. In this regard, the Myc transcription factors are intriguing therapeutic targets because they serve the unique and irreplaceable role of coordinating expression of the many diverse genes that, together, are required for somatic cell proliferation. Furthermore, Myc expression is deregulated in most-perhaps all-cancers, underscoring its irreplaceable role in proliferation. We previously showed in a preclinical mouse model of non-small-cell lung cancer that systemic Myc inhibition using the dominant-negative Myc mutant Omomyc exerts a dramatic therapeutic impact, triggering rapid regression of tumors with only mild and fully reversible side effects. Using protracted episodic expression of Omomyc, we now demonstrate that metronomic Myc inhibition not only contains Ras-driven lung tumors indefinitely, but also leads to their progressive eradication. Hence, Myc does indeed serve a unique and nondegenerate role in lung tumor maintenance that cannot be complemented by any adaptive mechanism, even in the most aggressive p53-deficient tumors. These data endorse Myc as a compelling cancer drug target.

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

“…Proof-of-principle experiments using a dominant-negative transgene have unequivocally established that targeting MYC will have high therapeutic efficacy for many tumors (30,31,45), but small molecules that directly inhibit c-MYC are not available. The bromodomain protein inhibitor JQ1 inhibits MYC transcription and suppresses hematologic malignancies, although it is not yet optimized for in vivo delivery (46,47).…”

“…Dominant-negative approaches targeting c-MYC function impair intestinal tumor formation, and c-Myc heterozygous mice show reduced tumor development in the Apc min/+ model (16,17). Transgenic expression of a dominant-negative allele of Myc, OmoMyc, has provided proof of principle that targeting MYC can eliminate tumors with minimal disturbance to normal tissue (30,31). However, translation of these benefits to human patients will require a small-molecule approach.…”

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

“…Sustained MYC activation in mice creates a state of oncogene addiction, while MYC withdrawal in established tumors, including liver carcinomas, leads to tumor involution (Shachaf et al 2004;Soucek et al 2008). Additionally, owing to its role in mediating oncogenic signals, MYC is required for the maintenance of some tumors in which it is not amplified, including murine lung adenomas driven by KRAS and leukemia driven by MLL-AF9 (Zuber et al 2011b;Soucek et al 2013). In principle, the identification of critical molecules and processes required for MYC action in cancer provides an alternative strategy for targeting MYC-driven tumors (Dawson et al 2011;Delmore et al 2011;Zuber et al 2011c).…”

Concepts to Target MYC in Pancreatic Cancer

“…Only mild and reversible toxicities in tissues with a high proliferation index were observed upon systemic MYC inhibition by Omomyc in mice, arguing for an existing therapeutic window (25). Importantly, inhibiting MYC in a Kras-driven lung cancer model eradicates tumors even in a p53-deficient background (26). Excitingly, no resistance mechanism toward Omomyc-dependent inhibition of MYC was detected.…”

“…Excitingly, no resistance mechanism toward Omomyc-dependent inhibition of MYC was detected. Therefore, MYC seems to be a nonredundant node of nononcogenic addiction, at least in certain tumor entities in mice (26). Whether potent genetic inhibition of MYC is effective in murine Kras-driven mouse models of PDAC in vivo is not published so far.…”