PI3K/Akt signaling promotes small-cell lung carcinoma (SCLC) growth, survival, and chemotherapy IOX2 chemical structure resistance (54).
The PI3K pathway is activated in multiple advanced cancers through inactivation of the PTEN tumor suppressor gene (6). Systematic analysis of kinase genes has identified mutations in PI3K p110 catalytic Inhibitors,research,lifescience,medical subunit gene PIK3CA in human cancers (3,21,23). These missense mutations, H1047R, E545K and E542K, cluster in two conserved gene locations, and are mutations that confer constitutive kinase activity (21,55). PIK3CA gene is also amplified at high frequencies in squamous cell lung carcinoma, head and neck, gastric, and cervical cancers (56). Carcinoma of the pancreas is the fourth Inhibitors,research,lifescience,medical leading cause of cancer mortality in the U.S. Unfortunately its survival has not improved substantially over the past thirty years, with median survival in the metastatic stage of six months (16,17). TK inhibitors have been shown to improve the outcome in patients with lung and pancreatic cancers (43). EGFR
overexpression by immunohistochemistry is significantly higher in pancreatic tumor cells when compared to normal pancreatic cells (7). Erlotinib is a human EGFR type Inhibitors,research,lifescience,medical 1 (HER1)/EGFR TK inhibitor. As a single first or second line agent pancreatic disease control for more than eight weeks was achieved in 20% of patients (57). The drug was approved by the FDA initially for advanced NSCLC, and in 2005 for advanced pancreatic cancer combined with gemcitabine (58). So far only erlotinib has Inhibitors,research,lifescience,medical been shown
to improve survival in pancreatic adenocarcinoma, with one-year Inhibitors,research,lifescience,medical survival of 23% in the erlotinib group compared to 17% with gemcitabine monotherapy (20). Cholangiocarcinoma is a rare and aggressive tumor that is similar to pancreatic adenocarcinoma, both in histological features and in clinical outcome (18,59,60). Philip et al. reported EGFR expression rate of 81% in patients with unresectable or metastatic biliary disease. Following anti-EGFR therapy, 17 percent of patients were progression Isotretinoin free at six months; however, EGFR expression in baseline tumor specimens did not correlate with treatment benefit (48,61). Gefitinib (Iressa), another EGFR inhibitor, inhibits pancreatic cancer cell growth through EGFR-dependent pathways and delays anchorage-independent growth and invasiveness (62). It was approved in Japan and the US for the treatment of NSCLC. The original rationale for its use was the observation that EGFR is abundantly expressed in lung carcinoma tissue in comparison to adjacent normal lung (63). However, EGFR expression as detected by immunohistochemistry is not an effective predictor of response to gefitinib (13).