Targeted therapeutic strategies in non-small cell lung cancer
Creators: name: Castellano, Gina Marie
Publisher: name: No Publisher Supplied
Year: 2022

description: Despite vast advances in the past ten years in the field of cancer pharmacology, the majority of patients with non-small cell lung cancer (NSCLC) still do not benefit from targeted therapies because their tumors lack clinically “actionable” targets, or they suffer from resistance and recurrence. Currently it is estimated that about 25% of LUAD patients benefit from targeted therapy – the majority of which can be attributed to the discovery and clinical implementation of EGFR tyrosine kinase inhibitors (TKIs). Approximately 20% of LUAD patients harbor activating EGFR mutations, making them eligible for TKIs as first line treatments, and this has resulted in markedly improved outcomes as compared to traditional chemotherapy in lung cancer (6,7). However, despite superior responses to EGFR-TKIs, most patients develop acquired resistance within 18 months (8,9). Here we describe a novel EGFR M766Q mutation that occurred in a 79-year-old woman who had disease progression during second-line treatment with osimertinib. Homology modeling suggested that EGFR M766Q could disrupt osimertinib binding. L858R/M766Q double-mutant cells were 12-fold more resistant to osimertinib, and more than 250-fold more resistant to erlotinib and afatinib, as compared to L858R-mutant cells. In contrast, double-mutant cells remained sensitive to neratinib and poziotinib at clinically relevant doses (IC50, 4.3 and 1.3 nM, respectively). This was corroborated by the effect of the TKIs on colony formation and EGFR signaling. These results demonstrated that acquisition of EGFR M766Q exon 20 mutation is a novel mechanism of acquired resistance to osimertinib. Conversely, among LUSC patients, only those with oncogenic driver BRAF V600E or KRAS G12C mutation are eligible to receive targeted therapy, which makes up a mere less than 1% of all LUSCs. The most common oncogenic driver event in LUSC is an activating mutation in PIK3CA, the gene encoding phosphatidylinositol 3-kinase (PI3K) catalytic subunit p110α, occurring in ~16% of cases. Despite this, approved targeted therapies are not yet available for PI3K-mutant NSCLC, primarily because PI3K pathway inhibitors induce the activation of regulatory feed-back loops, cross-talk with other oncogenic pathways, or were too toxic. Here we describe identification of DNA-PKcs as a therapeutic vulnerability in PIK3CA-mutant LUSC, which led us to test whether CC-115, a dual mTORC1/2 and DNA-PK inhibitor, sensitizes LUSC to the standard of care chemotherapy. We demonstrate that CC-115 synergizes with carboplatin in 6 of 14 NSCLC cell lines, primarily PIK3CA-mutant LUSC. Synergy was more common in cell lines that had decreased basal levels of activated AKT and DNA-PK. CC-115 sensitized LUSC to carboplatin by inhibiting chemotherapy-induced AKT activation and enhancing apoptosis particularly in PIK3CA-mutant cells lacking wild-type TP53. In addition, pathway analysis revealed that enrichments in the IFNα and IFNγ pathways were significantly associated with synergy. In multiple LUSC patient-derived xenograft and cell line tumor models, CC-115 plus platinum-based doublet chemotherapy significantly inhibited tumor growth and increased overall survival as compared to either treatment alone, at clinically relevant dosing schedules. Immunohistochemistry and immunoblot analysis of CC-115-treated tumors demonstrated decreased P-Th308-AKT, P-S473-AKT, P-S235/236-S6 and P-S2056-DNA-PKcs, showing direct pharmacodynamic evidence of inhibited PI3K/AKT/mTOR signaling cascades. Because PI3K pathway and DNA-PK inhibitors have shown toxicity in clinical trials, we assessed toxicity by examining weight and numerous organs in PRKDC-wild type mice, which demonstrated that the combination treatment does not exacerbate the clinically accepted side effects of standard-of care-chemotherapy. This preclinical study provides strong support for the further investigation of CC-115 plus chemotherapy in LUSC.