Director of Professional Education; and Co-Leader, Developmental Therapeutics Program, UCSF Helen Diller Family Comprehensive Cancer Center
Efim Guzik Distinguished Professorship in Cancer Biology, UCSF
Full Biosketch: Martin McMahon, PhD
Professor In Residence, Department of Cellular and Molecular Pharmacology, UCSF
(415) 502-1317 (lab)
(415) 502-3179 (fax)
1450 3rd St., MC 0128; PO Box 589001
San Francisco, CA 94158-9001
1450 3rd Street, HD-340; San Francisco, CA 94158
Research in Martin McMahon’s laboratory in the Helen Diller Family Comprehensive Cancer Center at Mission Bay is focused on a mechanistic understanding of the initiation, progression and treatment of cancers associated with mutational activation of KRAS, its key signaling effectors BRAF and PI3’-kinase and additional pro-tumorigenic pathways such as WNT→β-catenin→c-MYC signaling. To pursue these aims, we utilize complementary biochemical, molecular and cell biological techniques to examine the consequences of RAS pathway activation in genetically engineered mouse (GEM) models of human cancer or in cultures of normal or cancer-derived cells. Our long-term goal is to collaborate in the design and evaluation of new treatments for cancer patients in which constitutive RAS pathway signaling contributes to the aberrant behavior of the tumor cell.
What is the fate of the initiated tumor cell?
We have observed the paradoxical ability of sustained activation of the RAS-regulated RAF→MEK→ERK MAP kinase pathway to elicit arrest of the cell division cycle in primary, immortalized or even in cancer-derived cell lines, the last an example of “oncogene overdose” (4). Indeed, RAF activation in primary mouse or human fibroblasts leads to an irreversible cell cycle arrest that has been dubbed oncogene-induced senescence (OIS). Invariably, RAF-induced cell cycle arrest was accompanied by sustained elevation of cyclin-dependent kinase inhibitors (CKIs) of the INK4 or CIP/KIP family (e.g. p16INK4A or p21CIP1) that are required for cell cycle arrest. Experiments in cultured cells have been complemented using GEM models in which mutated BRAFV600E can be induced in cells of adult mice at normal physiological levels of expression and subject to normal patterns of splicing (1). Indeed, expression of mutated BRAFV600E in melanocytes or the pancreatic or lung epithelium led to an initial phase of cell proliferation leading to the formation of benign melanocytic nevi, pancreatic intra-epithelial neoplasias (PanIN) or benign lung adenomas (1-3). These benign lesions expressed markers of senescence, displayed signs of cell cycle arrest and rarely progressed to cancer, consistent with the notion that OIS can prevent progression of initiated benign tumor cells to frank malignancy. More recently, we have noted that the engagement of cell cycle arrest in benign BRAFV600E-induced adenomas is mediated by an insufficiency of WNT→β-catenin→c-MYC signaling (7). We are currently interested in mechanisms of OIS induction with an emphasis on the role of cell cycle regulators, alterations in WNT signaling and secretion of inflammatory cytokines as triggers for cell cycle arrest and senescence.
How do additional pro-tumorigenic genetic events cooperate with oncogenic KRAS or BRAF to promote malignant cancer progression?
Expression of mutated BRAFV600E cooperates with mutationally activated PIK3CAH1047R β-catenin or c-MYC or with silencing of tumor suppressors such as TP53, CDKN2A or PTEN for cancer development (2, 3, 5-8). Using our various models we are investigating mechanisms by which such genetic alterations cooperate for cancer progression. We suspect that cooperating genetic damage undermines the ability of oncogenic BRAFV600E to induce cell cycle arrest and senescence. However, it is also likely that there are multiple modes of cooperation involving suppression of programmed cell death, promotion of tumor angiogenesis. Recently, we generated BRafFA mice, carrying a Flp recombinase-activated allele of BRaf (9). These mice allow us to temporally dissociate BRAFV600E expression from Cre-mediated tumor suppressor gene silencing in a manner that more closely models the stepwise progression of human cancer. In addition, using BRafCAT mice, in which expression of oncogenic BRAFV600E is linked to expression of the fluorescent protein tdTomato, we can identify and isolate the earliest oncogene expressing initiated tumor cells and characterize their biochemistry and biology.
What are the mechanisms of response of tumors to pharmacologic agents targeted against RAS-regulated signaling pathways?
Since mutated RAS proteins have proven refractory to pharmacological targeting, considerable interest has focused on the protein and lipid kinases that transmit signals from activated RAS.GTP throughout the cell (10). Using pharmacological agents that target RAF, MEK, ERK, PI3’-kinase or AKT and are testing their ability to either prevent the onset of cancer, promote regression of established tumors or prevent the onset of drug resistance (2, 5, 8, 11). Such agents provide two advantages. First, they allow us to design pre-clinical trials in which the anti-cancer utility of such agents can readily be assessed either as single agents or in combination with conventional chemotherapy, other pathway-targeted agents or biologics and immunotherapies. Such studies will provide information useful for the design and evaluation of clinical trials in diseases such as melanoma and lung cancer, where there is evidence that these pathways are required for cancer maintenance. The other advantage is that such agents provide specific and selective research tools for the exploration of mechanisms of cancer maintenance by RAS-regulated signaling pathways. Furthermore, the complementary use of mouse models and cultured cells allow us to unravel both tumor cell autonomous and non-autonomous mechanisms of drug action.