Wednesday, April 16, 2014

Therapeutic Implications of Inhibiting Cdk4

  Recently, while I was perusing through the Wall Street Journal I stumbled across an article on a phase I study of a potential monotherapy for metastatic breast cancer patients. According to the AACR, Lilly Pharmaceutical's has developed a drug (LY2835219) with the aide of South Texas Accelerated Research Therapeutics that resulted in preventing tumor growth in 33 of 47 patients. The drug inhibits Cdk4. These articles fail to offer any information on the significance of targeting Cdk4 and not other Cdk's. Crucially, the data presented may be unreliable due to the small sample size.

  In order to validate these claims, I investigated the science behind the drug and discovered a study entitled "A Synthetic Lethal Interaction between K-RAS Oncogenes and Cdk4 unveils a Therapeutic Strategy for Non-small Cell Lung Carcinoma." This study was especially, enlightening in revealing what the article failed to articulate about the therapeutic potential of Cdk4 and how it augment cancer cell growth. In this study researchers implemented the synthetic lethal interaction hypothesis proposing,"disruptions of one gene will sensitize cells to disruption of another pathway while sparing cell that retain either one of the two functions"(Sherr 3693). Subsequently, researchers ablated Cdk2,Cdk4, and Cdk6 in mice by controlling gene expression. Only the inhibition of Cdk4 prompted a senescence response from lung cells with an activated K-RAS oncogene. Ultimately, the result of only inhibiting Cdk4 was the prevention of tumor growth. Moreover, the study compared these results to the selective inhibitor drug PD0332991 that targets both Cdk4,6 to conclude that the targeting of Cdk4 is a more potent method to induce cell senescence.

Figure C and D below demonstrates the effects of PD0332991 compared to vehicle. Figure C is an immunohistochemical analysis of Cdk4 specific phosphorylated Rb in a lung section from a K-Ras activated wild type mouse after 30 days of treatment with vehicle (left) or 150mg/kg of PD0332991 (right). Figure D is a Western blot analysis of individual tumors from the lung of a K-Ras activated wild type after 30 days of treatment with vehicle (T1-T3) or 150 mg/kg of PD0332991 (T1-T6) with antibodies specific for pRb phosphorylated residues Ser 807 and Ser 811.

It may be concluded that tumors exposed to PD0332991 did decrease the inhibition of pRb in the Cdk4 specific Ser 807 and Ser 811 residues. However, the tumors exposed to PD0332991 did not express SA-beta galactosidase or an increase in tumor suppressors such as p53 or ARF. SA beta galactosidase is commonly used to determine if senescence is occurring. Since SA beta galactosidase is not expressed it appears that no senescence is occurring. In comparison the inhibition of Cdk4 resulted in the expression of SA-beta galactosidase. Furthermore, Cdk4 is a known inhibitor of pRb. This study would suggest a synthetic lethal interaction occurs with the loss of Cdk4 for K-RAS because inhibition of Cdk4 is the best means to induce cell senescence. 

   The science behind Lilly's new drug appears promising as inhibition of Cdk4 is central to deterring cell growth. Still, many questions regarding how to implement the inhibition of Cdk4 remain unanswered. 


Puyol,Marta, Alberto Martin Pierre Dubus, Francisca mulero, Pilar Pizcueta, Gulfaraz Khan, Carmen Guerra, David Santamaria, and Mariano Barbacid. "A Synthetic Lethal Interaction between K-Ras Oncogenes and Cdk4 Unveils a Therapeutic Strategy for Non-small Cell Lung Carcinoma."Cell. 18. (2010): 63-73 

"New Drug Demonstrates Early Promise in Metastatic Breast Cancer". AACR.April 6, 2014.  

Sherr, Charles J. "The Pexcoller Lecture: Cancer Cell Cycles Revisted". AACR.60.(2000):3689-
3695.Web 16 Apr. 2014. 

"Two Drugs Show Promise in Slowing Breast Cancer". Rockoff Jonathan D. and Ron Winslow. Wall Street Journal. April 6, 2014.