All cancers were void of T790M mutations, mutationsmutations or other known confounding genetic abnormality that would be expected to negatively impact response

All cancers were void of T790M mutations, mutationsmutations or other known confounding genetic abnormality that would be expected to negatively impact response. benefit from EGFR inhibitors. These findings suggest assessment of BIM levels in treatment na?ve tumor biopsies may indicate the degree of benefit from single-agent kinase inhibitors in multiple oncogene-addiction paradigms. mutant lung cancers and amplified breast cancers. In both malignancy types, tyrosine kinase inhibitors (TKIs) or antibodies that disrupt the function of the corresponding receptor tyrosine kinase (RTK) are effective treatments (1C4). Other paradigms of oncogene dependency have more recently emerged, such as GDC-0980 (Apitolisib, RG7422) translocated lung cancers treated with the ALK TKI critzotinib (5). Although these therapies are highly successful in these populations as a whole, there is a high degree of heterogeneity within each subtype. For example, although some patients benefit from a targeted therapy for much longer than one year, some only benefit for a few months. In addition, 30C40% of patients with mutant non-small lung cancers (NSCLCs) and translocated lung cancers fail to achieve RECIST criteria responses to targeted therapy, for largely unknown reasons (5). The biology underlying this heterogeneity of clinical benefit is not well understood. In addition, biomarkers that identify those who do not benefit as greatly from single-agent targeted therapy would aid in directing them to novel therapeutic strategies. The evasion of apoptosis is a hallmark of cancer and is often caused by disruptions in the intrinsic surveillance system regulating the survival of a cancer cell. Critical to this surveillance system is a group of Bcl-2 like proteins that connect growth factor signaling pathways with the mitochondria, the epicenter of apoptosis GDC-0980 (Apitolisib, RG7422) (6). In oncogene-addicted cancers, the growth and survival signals originating from the oncogene lead to the regulation of both the expression and the interactions of Bcl-2 family members. When the balance of pro- and anti-apoptotic proteins changes to favor apoptosis, as it often does following effective targeted therapy, two terminal members of the Bcl-2 family, Bak and Bax, homo-and/or hetero-dimerize to form porous channels in the mitochondria, committing the cell to apoptosis (6). Recent data has demonstrated that the pro-apoptotic Bcl-2 family member BIM is a particularly critical mediator of targeted therapy-induced apoptosis in both blood and solid tumor cancers (7C17). This BH3 only Bcl-2 family member directly binds to the antagonistic pro-apoptotic Bcl-2 members, such as Mcl-1 and Bcl-2, by binding into their hydrophobic clefts, countering their pro-survival effects (18). BIM also interacts directly with Bax, activating it to promote cell death (19). In cancers addicted to receptor tyrosine kinases, the regulation of key intracellular signaling pathways (e.g., PI3K-AKT and MEK-ERK) is under strict control of the corresponding RTK. Pharmacological inhibition of the RTK with targeted therapies leads to suppression of these signaling pathways and often results in apoptosis (7,20C21). In mutant NSCLC cells, we and others have demonstrated that apoptosis is triggered by tipping the scale of pro- and anti-apoptotic Bcl-2 family members in favor of pro-apoptotic signaling (7C11). BIM levels increase following MEK-ERK pathway suppression, and Mcl-1 levels decrease following PI3K-mTORC pathway inhibition downstream of EGFR (7). Normally, the MEK-ERK pathway suppresses BIM expression by direct phosphorylation of BIM, leading to proteosomal degradation (22,23). The upregulation of BIM due to suppression of MEK-ERK signaling is essential for the induction of apoptosis, but in mutant cancers, it is not sufficient. Reducing levels of cellular BIM with siRNA and shRNA blocks TKI-induced apoptosis (7C11). Other successful targeted therapy paradigms have also demonstrated an integral role for BIM in promoting apoptosis in response to targeted therapies, including mutant colorectal cancers (13), mutant melanoma cancers (14,24,25), translocated chronic myeloid leukemia (CML) cancers (15), and translocated lung cancers (26). Importantly, evidence from in vivo studies suggests, but does not prove, that the apoptotic response may be an essential contributor to marked tumor regressions in vivo upon treatment with targeted therapies (7,27). Thus, we hypothesize that patients with oncogene-addicted cancers that undergo the most dramatic apoptotic responses to kinase inhibitors may enjoy the greatest benefit from kinase inhibitors. However, there has been no biomarker identified to date that accurately predicts which EGFR and HER2 addicted cancers are most likely to undergo robust GDC-0980 (Apitolisib, RG7422) apoptosis in response to to TKIs. Here, we describe the identification of pre-treatment BIM levels as a Rabbit Polyclonal to ERCC5 functional biomarker that predicts the induction of apoptosis in several oncogene-addiction paradigms. Assessment of this biomarker in clinical samples effectively distinguished the benefit that patients derived from single-agent EGFR TKIs. Results Pre-treatment BIM.