Abstract PL05-03: Future challenges of targeted therapy
Authors: McCormick Frank 
Published: May 2019

Abstract
Successes and failures of the first generation of targeted therapies suggest ways in which we will need to develop this field in the future. At least four major challenges have emerged for the next generation of targeted therapies:Rapid emergence of drug resistant variants in tumors driven by a dominant driver mutationLack of response to target inhibition because of co-existent mutations in other pathwaysResistance through adaptation and/or loss of oncogene addictionDriver oncoproteins or pathways are undruggable
Solutions exist for each of these problems, but each raises new issues, complexities and costs.
Rapid emergence of drug resistant variants in tumors driven by a dominant driver mutation. This phenomenon was anticipated by prior experience with earlier targeted therapies (methotrexate, etc) , and has been extensively analyzed and modeled in imatinib-treated CML (see Michor et al, Nature. 435, 1267–70, 2005, for example) and other indications. A disturbing conclusion is that a tumor with as few as 100,000 cells (0.1 ul) already contains drug-resistant variants prior to treatment in 13% cases: tumors with 1,000,000 cells (1 ul) will fail through pre-existing drug resistance in 90% cases. While it is encouraging that these tumors respond dramatically to treatment (they are addicted to the dominant driver), durable responses, or cures, will certainly require as many as three effective drugs in combination to prevent outgrowth of resistant variants. The rapid emergence of resistant clones, which appear to be identical from the parental tumor except for drugresistant mutations, argues against the proposal that therapies fail because of rare stem-cell like fractions that are relatively indifferent to targeted agents. Mutations in the PTEN or p53, or other proteins in these pathways, can defeat the effects of drugs that appear to inhibit driver mutations effectively (see Mellinghoff et al, N Engl J Med. 353, 2012–24, 2005, for example, for discovery that loss of PTEN defeats the effects of EGF-R inhibitors in glioblastoma). Activation of the pro-survival PI 3′ kinase pathway is thought to account for this effect, suggesting that drugs targeting this pathway should be used in combination of EGF-R inhibitors, or other inhibitors of ‘driver’ proteins, and indeed, preclinical models strongly supports this hypothesis and clinical trials are already underway with several combinations. The contribution made by p53 mutation is more complicated, as this protein can affect cell cycle or survival. Loss of p53 can therefore sensitize cells to drugs that act by poisoning cells in S-phase, or de-sensitize cells to drugs that are expected to promote cell death. In any case, this problem demands knowledge of all the relevant mutations in a tumor, and combinations of drugs tailored accordingly. Resistance through adaptation or loss of oncogene addiction. The discovery that tumor cells appear addicted to driver mutations provided an unexpected degree of selectivity for targeting pathways that are essential components of normal cells. This addiction appears to be due to suppression of feedback loops that normally regulate these pathways. For example, hyper-activation of the Raf MAPK pathway leads to down regulation of EGF-R signaling and hence the PI 3′ kinase pathway and cell survival. Blocking the Raf MAPK pathway can therefore lead to dramatic and selective cell killing (see Solit et al, Nature 439 358–62 2006, for example). However, inhibition of driver protein activity restores cells to a more normal state, and they lose oncogene addiction. Inhibition of MEK, for example, leads to increases in Akt activity, via EGF-R activation: this will be discussed in detail. Restoration of feedback loops can therefore defeat targeted therapy. A solution to this example might be a combination of MEK inhibitor with an EGF-R inhibitor, a combination that would have seemed illogical before the importance of feedback loops was appreciated. Feedback loops regulate signal transmission at multiple levels. In the Ras/Raf/MAPK pathways, a number of important loops have been identified: ERK phosphorylates receptor tyrosine kinases, Sos, and Raf kinases, for example. In tumor cells harboring activated alleles of Ras or B-Raf, these feedback loops are expected to hyper-activated also. Conversely, when kinases in this pathway are blocked by pharmacologic agents, loss of feedback is likely to hyper-activate upstream elements, with important consequences for therapy In addition, clinical responses to EGF-R inhibitors suggest that these receptors have a growth-suppressing effects in tumors with mutant KRAS. This unexpected result has major implications for cancer therapy using kinase inhibitors, and suggests signaling relationships that had not been previously recognized, even in a well studied pathway such as EGF-RAS. Likewise, the totally unexpected induction of squamous cell carcinoma in patients being treated with Raf kinase inhibitors reveals a level of regulation of BRAF and CRAF that had not been appreciated previously, but requires re-examination of these pathways in preclinical models and in new clinical trials. These adaptive responses reveal our limited knowledge of signaling pathways and challenge us to use new and more systematic ways of predicting clinical responses to targeted therapies and designing clinical protocols accordingly. In any event, it is clear that effective treatment of cancer my blocking intracellular signaling proteins is likely to demand more than one specific drug, for reasons that are quite distinct than those discussed above. Perhaps the major obstacle to treating cancer in general is the fact that most cancer targets, defined by genetic screens or by biochemical analysis, are not amenable to therapeutic intervention: they are undruggable. This restriction is of major concern considering that cancer needs to be treated by attacking two or more targets at once, and perhaps several pathways at once, for the reasons discussed above. In most cases, at least one of these targets is likely to be undruggable. Success has been achieved in identifying drug candidates that block Mdm2/p53 interactions and Bcl-2 partner interactions, but these have been technical challenges of the highest order, and have not yet proven effective in the clinic. Solutions to this major problem may come from new ways of doing chemistry, or from new platforms altogether, such as systemic use of RNA interference. These issues will be discussed.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):PL05-03.