These recent abstracts address a couple of recent talking points:
1) Why Pfizer gave up Tarceva versus giving up another EGFr inhibitor, and
2) Why the blockade of EGFr may offer diminished results over time. This is fuzzy still, with multiple explanations possible, including MZ's suggestion of a mutation of the ATP site. Another possibility is that many TKI's, including Tarceva, don't block all the erbB receptors they needed to maintain efficacy. CI 1033 and PKI 166 appear to do this. I haven't yet looked at whether mAbs such as ABX-EGF do that. Then there's the recent work suggesting irreversible TKI's are more efficacious than reversible ones.
>>Cancer Res 2002 Jun 1;62(11):3151-8
The efficacy of ErbB receptor-targeted anticancer therapeutics is influenced by the availability of epidermal growth factor-related peptides.
Motoyama AB, Hynes NE, Lane HA.
Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
The ErbB1 and ErbB2 receptor tyrosine kinases (RTKs) play important roles in the development of numerous types of human cancer and, as such, have been pursued as anticancer targets. To understand the mechanisms contributing to the response of tumor cells to receptor-directed therapeutics, the sensitivity of the ErbB receptor-overexpressing tumor cell lines BT474 and MKN7 to specific inhibitors has been examined. The inhibitors used included monoclonal antibody (mAb) 4D5, which targets ErbB2, and the small molecular weight kinase inhibitors CGP59326 and PKI166, which block the activity of ErbB1 or both ErbB1 and ErbB2, respectively. We had reported previously that although both BT474 and MKN7 cells overexpress ErbB2, only BT474 cells show an antiproliferative response to mAb 4D5 treatment. Here, we show that MKN7 cells, which also overexpress ErbB1, are sensitive to CGP59326, displaying a 60% decrease in their proliferation after treatment with this inhibitor. Most carcinomas express multiple ErbB receptors as well as EGF-related ligands, a situation favoring activation of numerous combinations of ligand-activated receptors. Considering this, the sensitivity of MKN7 and BT474 cells to CGP59326 and mAb 4D5, respectively, was also tested in the presence of exogenous ligands. Treatment of MKN7 cells with CGP59326 in the presence of heregulin (HRG), which activates ErbB2/ErbB3, attenuated the antiproliferative effect of CGP59326 by 50%; MKN7 cells engineered to overexpress ErbB3 were completely rescued from CGP59326 by HRG. Likewise, BT474 cells treated with mAb 4D5 in the presence of epidermal growth factor, betacellulin, and HRG were rescued from its antiproliferative effects by 57, 84, and 90%, respectively. In both MKN7 and BT474 tumor cells, the degree of ligand-induced rescue from the inhibitors correlated with the potency of ErbB receptor activation and stimulation of the PI3K and MAPK intracellular signaling pathways. In comparison with the monospecific agents, treatment with the bispecific ErbB1/ErbB2 kinase inhibitor PKI166 almost completely prevented the EGF-related ligand-induced bypass of the proliferation block in the MKN7 and BT474 cells. These data suggest that the efficacy of anticancer drugs that block a single ErbB receptor may be compromised by the presence of exogenous epidermal growth factor-related ligands, a phenomenon that could be averted by simultaneously blocking multiple ErbB receptors.<<
>>Semin Radiat Oncol 2002 Jul;12(3 Suppl 2):33-6
Small-molecule tyrosine kinase inhibitors as radiosensitizers.
Lawrence TS, Nyati MK.
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.
The discovery of a class of highly selective and potent compounds called the 4-anilinoquinazolines has led to the development of small-molecule tyrosine kinase inhibitors as potential anticancer agents. These agents inhibit essential cellular pathways in growth factor expression and can be administered as an oral formulation. Some of these agents, such as ZD1839 and OSI-774, tend to bind in vitro only to the epidermal growth factor receptor tyrosine kinase while others, such as CI-1033, bind to multiple members of the ErbB family. The first clinical compounds that were developed, such as ZD1839, were reversible inhibitors. More recently, irreversible compounds have been developed that may be more effective at producing long-term suppression. Very little published work is available concerning the interaction of small-molecule tyrosine kinase inhibitors with radiation. This article presents our data on the interactions of CI-1033 with radiation.<<
emphases mine
PK166 is a Novartis candidate. Of course, Tarceva and Iressa are ahead in the clinic. It will be interesting to see how sales of Iressa go in Japan, where it is approved as a monotherapy. Also, we should get an update regarding the time of completion for the pancreatic cancer trial at any time (the May PR said late summer), as the trial centers should all be activated and enrollment completed very soon.
Cheers, Tuck |
