A major treatment modality in the advanced disease setting is chemotherapy, with cisplatin-based regimens playing significant roles in the cancer management strategy of a number of cancers, including ovarian cancer, mesothelioma and non-small cell lung cancer. However, the majority of advanced cancer cases relapse and fail therapy due to the onset of cisplatin resistance, and patients eventually succumb to their disease. The most recent advance about two decades ago was the inclusion of taxol to the platinum regimen, but this has only provided short-term incremental benefit without impacting the 5-year survival rate. Thus, cisplatin resistance is a significant drawback, and there is a desperate need to understand the causes of resistance, so new agents can be developed. A major understanding emerging from our work is that wild-type p53 features prominently in the resistance phenotype and this represents a major puzzle why the apoptotic function of p53 is being inhibited. Since many advanced and refractory cancer disease types include substantial numbers of tumors that harbor wild-type p53, there is reason to believe that a common defect in a key gene or pathway may be the cause of p53 failing to become functionally activated. Based on the strong relationship of mutual exclusivity, tumors with wild-type p53 are likely to have defective Chk2 expression, and this defect will impact post-translational modification of p53 that is essential for stabilization and stimulation of its function. Indeed, wild-type p53 in cisplatin-resistant tumor cells often demonstrates defective function. Since specific cancers have intrinsic affinity for platinum drugs, we hypothesize that defective Chk2 expression prevents stabilization and/or stimulation of wild-type p53 in cisplatin-resistant cancers, and that platinum analogs can be designed to activate an alternative kinase to maximally restore p53 inducibility and cytotoxic activity. We will address this hypothesis through three specific aims: 1) Characterize cisplatin resistance as related to defective Chk2 in tumor panels harboring wild-type p53; 2) Identify the kinase activated by platinum analogs that restores p53 function in cisplatin-resistant cells; and 3) Establish structure-activity relationships for lead optimization and identify an analog that maximally stabilizes and stimulates wild-type p53 in resistant Chk2-defective tumor cells. Based on mouse models, activation of wild-type p53 is sufficient to kill tumor cells, and this raises the potential that targeting cisplatin resistance through a mechanism-directed drug development approach will restore wild-type p53 function and significantly increase response and 5-yr survival rates.

Public Health Relevance

Advanced solid cancers are treated with cisplatin-based regimens, but the response is not durable and up to 90% of the patients may die as the tumor demonstrates resistance to therapy. Cancers that still harbor the normally-apoptotic wild-type p53 gene are the most resistant, and we will investigate why p53 is not functioning to allow rational therapies to emerge. Our mechanism-based strategy will identify drugs that will have potential for curative therapies to be realized.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Kondapaka, Sudhir B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
Internal Medicine/Medicine
Other Domestic Higher Education
United States
Zip Code
Xie, Xiaolei; He, Guangan; Siddik, Zahid H (2017) Functional Activation of Mutant p53 by Platinum Analogues in Cisplatin-Resistant Cells Is Dependent on Phosphorylation. Mol Cancer Res 15:328-339
Altaf, Muhammad; Monim-Ul-Mehboob, Muhammad; Kawde, Abdel-Nasser et al. (2017) New bipyridine gold(III) dithiocarbamate-containing complexes exerted a potent anticancer activity against cisplatin-resistant cancer cells independent of p53 status. Oncotarget 8:490-505
Bhatt, Michelle; Ivan, Cristina; Xie, Xiaolei et al. (2017) Drug-dependent functionalization of wild-type and mutant p53 in cisplatin-resistant human ovarian tumor cells. Oncotarget 8:10905-10918
Xie, X; Lozano, G; Siddik, Z H (2016) Heterozygous p53(V172F) mutation in cisplatin-resistant human tumor cells promotes MDM4 recruitment and decreases stability and transactivity of p53. Oncogene 35:4798-806
Thiabaud, Gregory; McCall, Rebecca; He, Guangan et al. (2016) Activation of Platinum(IV) Prodrugs By Motexafin Gadolinium as a Redox Mediator. Angew Chem Int Ed Engl 55:12626-31
Farooqi, Ammad Ahmad; Siddik, Zahid H (2015) Platelet-derived growth factor (PDGF) signalling in cancer: rapidly emerging signalling landscape. Cell Biochem Funct 33:257-65
Kim, Eric S; Tang, XiMing; Peterson, Derick R et al. (2014) Copper transporter CTR1 expression and tissue platinum concentration in non-small cell lung cancer. Lung Cancer 85:88-93
Thiabaud, Grégory; Arambula, Jonathan F; Siddik, Zahid H et al. (2014) Photoinduced reduction of Pt(IV) within an anti-proliferative Pt(IV)-texaphyrin conjugate. Chemistry 20:8942-7
He, G; Kuang, J; Koomen, J et al. (2013) Recruitment of trimeric proliferating cell nuclear antigen by G1-phase cyclin-dependent kinases following DNA damage with platinum-based antitumour agents. Br J Cancer 109:2378-88
Moreno-Smith, Myrthala; Lee, Sun Joo; Lu, Chunhua et al. (2013) Biologic effects of dopamine on tumor vasculature in ovarian carcinoma. Neoplasia 15:502-10

Showing the most recent 10 out of 15 publications