Agents in the preclinical development stage for non-small cell lung cancer

Abstract

Despite recent advancements in identifying distinct molecular subtypes with driver oncogenes and advances in developing targeted treatments such as epidermal growth factor receptor and anaplastic lymphoma kinase inhibitors, current therapeutic approaches for tumors with no driver mutation have achieved a plateau of effectiveness. Thus, the overall outlook of lung cancer survival for most patients remains dismal. Moreover, the inevitable acquisition of resistance to targeted therapies has prompted significant efforts to develop second-generation inhibitors. In recent years, several agents for targeted therapy of lung cancers are rapidly migrating from bench to bedside and multiple small molecule inhibitors with activity against distinct receptors, genes or molecular pathways have been developed.

Keywords:

• molecular agents
• non-small cell lung cancer
• preclinical compounds
• targeted therapy

Financial & competing interests disclosure

C Gridelli has received honoraria as a member of the speaker’s bureau and advisory board for Eli-Lilly, Roche and Boehringer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Several agents with activity against distinct receptors, genes or molecular pathways have been developed.

• Gö6976, PKC412 and CEP-701 inhibit the T790M mutant EGFR cells and bind with less or no affinity to wild-type EGFR.

• CH5164840, a novel heat shock protein 90 inhibitor, is highly effective in combination with erlotinib against tumor with EGFR T790M mutation.

• ASP3026 and AZD3463 induce tumor regression in cells expressing EML4–ALK with L1196M mutation. ASP3026 enhances the paclitaxel and pemetrexed tumor activity.

• PF-06463922 has a strong activity against all known ALK and ROS1 mutant cells that are resistant to crizotinib. It penetrates the blood–brain barrier.

• NPS-1034 inhibits the growth of gefitinib-resistant cell lines, when combined with gefitinib.

• ATN-224 shows a significant decrease in lesion numbers and overall tumor burden in KRAS-driven mouse models.