Acquired resistance

Chemotherapy has been the mainstay for treatment of small cell lung cancer (SCLC)—a highly aggressive subtype of lung cancer—for the past three decades. SCLC responds well to initial treatment but inevitably comes back. No targeted therapy is currently available for patients with SCLC. Dr. Lehman is studying how SCLC becomes resistant to chemotherapy. His research will further our understanding of chemotherapy resistance and identify novel targets for SCLC treatment.

Drs. Byers and Gibbons have discovered that lung cancer cells acquire the ability to hide from the immune system during epithelial-to-mesenchymal transition—a process through which cancer cells develop the ability to spread to other parts of the body (metastasis). The LUNGevity award will help Drs. Byers and Gibbons study the effect of a new drug that can reverse the EMT process and make lung cancer cells more visible to the immune system.

Dr. Pao’s research may determine whether specific mutations in tyrosine kinase genes make lung tumors vulnerable to EGFR-TKIs. A comprehensive analysis of the tyrosine kinase in lung cancers could also lead to new opportunities for drug development and more personalized molecularly targeted therapies.

Dr. Haura’s hypothesis is that the tyrosine kinase SRC and the protein Stat3 are ideal targets for cancer therapy in lifelong non-smokers who develop lung cancer resulting from EGFR mutations. He is conducting experiments to demonstrate that inhibitors of SRC and/or Stat3 can kill cancer cells. Such inhibitors may have additive effect when used in connection with EGFR inhibitors such as gefitinib or erlotinib.

By modeling acquired resistance to gefitinib and erlotinib in the laboratory using a non-small cell lung cancer (NSCLC) cell line that is sensitive to these drugs, Dr. Sharma hopes to uncover the molecular basis for acquired resistance of NSCLC to these targeted therapeutics as well as clues to overcoming this resistance.

Dr. Meyerson is exploring how a mutation in the EGFR cells can lead to cancer as well as what the mechanisms are for acquired resistance to EGFR therapies.

Dr. Dang is studying the anti-tumor effect of gamma-secretases inhibitors, compounds that inhibit activation of the Notch pathway that is active in lung cancer cells. She is studying its effect both alone and in combination with traditional chemotherapy and targeted therapy.

EGFR tyrosine kinase inhibitors (TKIs) are the mainstay for treatment for non-small cell lung cancer (NSCLC) patients whose tumors have mutations in the EGFR gene. Unfortunately, cancer cells eventually become resistant to TKIs. Dr. Krysan's laboratory has discovered that NSCLC cells produce a chemical called PGE2 that helps lung cancer cells grow in the presence of EGFR TKIs. This suggests that PGE2 helps cancer cells develop acquired resistance to TKIs. Dr. Krysan’s current research is to determine how PGE2 works.

Patients with EGFR mutations are treated with EGFR drugs such as gefitinib (Iressa) and erlotinib (Tarceva). However, the cancer cells eventually develop resistance to these drugs. Dr. Sharma is  aiming to understand the processes by which non-small cell lung cancer cells develop resistance to gefitinib and erlotinib as well as  how these processes can be targeted to develop new therapeutic strategies for patients in whom gefitinib and erlotinib have failed.

The PARP protein is a protein that protects cancer cells from being killed by chemotherapy. Dr. Brandes is determining how drugs that stop the PARP protein can be used for targeted therapy of non-small cell lung cancer.