Sreenath V. Sharma, PhD
Assistant Professor of Medicine
Harvard Medical School
Assistant in Genetics
Center for Cancer Research
Targeted Anti-cancer Therapeutics on Epidermal Growth Factor Receptor (EGFR)
Our lab is interested in the general phenomenon of targeted anti-cancer therapeutics with particular emphasis on Epidermal Growth Factor Receptor (EGFR) and its targeted inhibition by Gefitinib and Erlotinib in the treatment of Non Small Cell Lung Cancers (NSCLC). The anti-tumor activity of targeted inhibitors of receptor tyrosine kinases stems from the fact that these tumors are addicted to the oncogene for their growth. “Oncogene addiction” refers to the acquired dependency of cancer cells on a single cellular pathway for survival or sustained proliferation. However, a molecular mechanism to explain oncogene addiction has been elusive.
Our recent studies show that differential attenuation rates of pro-survival and pro-apoptotic signals in oncogene-dependent cells contribute to cell death following acute oncogene inactivation, a phenomenon we refer to as “Oncogenic Shock”. Our findings suggest that the apoptotic response to oncogene inactivation by targeted inhibitors reflects a transient imbalance in survival and apoptotic oncogenic outputs due to a “competition” between relatively short-lived survival signals and longer-lived apoptotic signals. Moreover, these observations implicate a common profile of signal attenuation in dependency on distinct oncogenes, and suggest that “addiction” associated with apoptotic cell death reflects an active, as opposed to a passive process.
Our experience with Gefitinib and Erlotinib have taught us that while RTKs are very useful targets for therapeutic intervention, their inhibition may be efficacious in only a small subset of patients and that mutations in RTKs may be one of the useful predictors of response to RTK-targeted inhibitors (RTKIs). However, the small numbers of patients that derive benefit from RTKIs points to some deficiencies in the old way of doing things and suggest a slight reorientation in our approach to drug discovery. One overarching theme to emerge is that every step of the process (analysis for mutations in RTK genes, screening for novel targeted therapeutics or identification of addicting oncogenes) has to be carried out on larger numbers of tumor samples or cell lines so as not to miss the rare responders. A simple calculation reveals that in order to see the 10% response to Gefitinib or Erlotinib, typically seen in NSCLC patients, a cell-based drug screen would require a minimum of 100 and ideally 1000 different NSCLC-derived cell lines. This is way beyond anything that is currently being used in cell-based screens. Given the current cell-based screening strategies that generally involve a few cell lines representative of each tumor type, it is likely that Gefitinib or Erlotinib would never have been picked up as a “hit”. A similar rationale can be applied for the number of tumor samples that would need to be analyzed in order to detect mutations in EGFR in an unselected cohort of NSCLC patients. Recent studies underscore the value of large-scale genomic analysis of large number of tumors of a particular type in highlighting the complexity of the cancer landscape and more importantly in pinpointing the limited number of specific genetic alterations that are key to the genesis of these tumors. In keeping with this theme, The Center for Molecular Therapeutics at the Massachusetts General Hospital Cancer Center has a cancer cell line collection of over 1000 human tumor-derived cell lines. These cell lines are being used as a platform for the profiling of existing and novel targeted therapeutics. We hope to integrate the drug screening data on these cell lines with expression arrays and array CGH data. It is conceivable that such an approach, applied across a large panel of cell lines derived from different tumor types, might reveal addicting oncogenes in common, whose ablation might have potent therapeutic effects against a particular tumor type. Our initial studies reveal that responses of cancer-derived cell lines to a variety of targeted therapeutics are primarily genotype-based. These findings, if validated would represent a paradigm-shift in cancer treatment away from organ-based cancer therapy to a more genotype-based therapeutic stratification of cancer patients.
One of the major limitations of RTKIs in the treatment of cancer is the rapid emergence of resistance. We are very interested in developing in vitro models of resistance to a wide variety of RTKIs and understanding the molecular basis that underlies this phenomenon. We hope that such an understanding would be crucial not only to the better application of these agents but also provide alternatives to the emergence of resistance when it does occur in patients.
Sreenath V Sharma, PhD
Principal InvestigatorGroup Members