Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver events and molecular properties via multiple time points from same case PDXs. Here, we report on dynamic genomic landscapes and pharmacogenomic associations, including associations between activating oncogenic events and drugs, correlations between whole-genome duplications and subclone events, and the potential PDX models for NCI-MATCH trials. Lastly, we provide a web portal having comprehensive pan-cancer PDX genomic profiles and source code to facilitate identification of more druggable events and further insights into PDXs’ recapitulation of human tumors.

No abstract

No abstract

Sotorasib (AMG 510) is the first KRAS inhibitor to be FDA-approved for the treatment of KRASG12C mutant lung adenocarcinomas which comprise ~42% of KRAS mutations in lung adenocarcinomas. Preclinical studies have shown that within hours of KRASG12C inhibition, synthesis of new KRASG12C protein and increased KRAS signaling was observed, leading to enhanced tumor cell growth and survival. This appeared to be due, at least in part, to a feeback loop leading to activation of EGFR signaling but the role of other ErbB family members including ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4) has not been fully evaluated. We hypothesize that short-term adaptation to KRAS inhibition is driven by multiple ErbB family members, and that the combination of pan-ErbB inhibitors with KRASG12C inhibitors could enhance KRASG12C inhibitor activity and prolong survival in preclinical models harboring KRASG12C mutations to a greater extent than more specific EGFR inhibitors. To investigate the role of different ErbB family members in this feedback signaling, we evaluated the impact of an EGFR specific inhibitor, erlotinib, an EGFR/HER2 inhibitor, afatinib, or pan-ErbB inhibitor (EGFR/HER2/3/4), poziotinib on anti-tumor activity of KRASG12C inhibitors in KRASG12C mutant NSCLC cell lines. We initially tested the different inhibitors in combination with sotorasib and adagrasib (MRTX849) and calculated the BLISS index (BI) for each drug pair matrix, using SynergyFinder. We found that when combined with either sotorasib or adagrasib, poziotinib had a synergistic effect (BI>10) in H23 (BI: 17, p=0.01), HCC44 (BI: 11, p=0.04), and H1792 (BI: 13, p=0.01) and an additive effect (BI= -10–10) in H2122 (BI: 2.8). Afatinib and erlotinib were additive in H23 (BI: 9.2 & 9.4), HCC44 (BI:8.8 & 7.9), H2122 (BI: -4.5 & -3.3) and H1792 (BI: 6.6 & 3.3). Poziotinib yielded a higher BI across all four cell lines compared to afatinib (p<0.0001) or erlotinib (p=0.0004). To determine if poziotinib prevented upregulation of ErbB-signaling after treatment with KRASG12C inhibitors, we treated KRASG12C mutant cell lines (NSCLC: H23 and Bladder Cancer: UM-UC-3) with KRASG12C inhibitors, sotorasib or adagrasib, for four hours and found by Western blotting that phosphorylated EGFR, HER2, HER3, and HER4 were increased after treatment. The addition of 10 nM poziotinib prevented the upregulation of phosphorylated EGFR, HER2, HER3, and HER4 in both cell lines. Together these data demonstrate that inhibition of EGFR, HER2, HER3, and HER4 signaling by the pan-ErbB inhibitor poziotinib resulted in greater synergy with KRASG12C inhibitors than EGFR or EGFR/HER2 inhibitors and highlight the potential importance of HER3 and HER4, in addition to EGFR and HER2, in feedback signaling after KRAS G12C inhibition. Additional studies of pan-ErbB and ErbB-specific inhibitors with KRASG12C inhibitors are warranted to determine tolerability and optimal dosing to prolong survival in KRAS mutant cancers. Citation Format: Jacqulyne P. Robichaux, Ana Galan-Cobo, Ried T. Powell, Kelly A. Gale, Jun He, Fahao Zhang, Monique B. Nilsson, Xiang Zhang, Mary M. Sobieski, Nghi Nguyen, Stephan C. Clifford, John V. Heymach. Pan-ErbB inhibition enhances activity of KRASG12C inhibitors in preclinical models of KRASG12C mutant cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P256.

Background: Oncogenic KRAS mutations occur in 50% of colorectal cancer (CRC) patients and have long been considered undruggable. Novel covalent inhibitors targeting the KRASG12C mutation have been developed, presenting a unique opportunity to directly target KRAS. However, clinical trials focusing on sotorasib reveal that KRASG12C inhibitors are only modestly active in CRC compared to lung cancer patients with response rates being 7% and 54%, respectively. Adaptive and acquired feedback has contributed to the diminished therapeutic efficacies observed in CRC patients. Recent studies have shown that receptor tyrosine kinases may be the conduit for adaptive feedback to KRASG12C inhibition, with EGFR being the focus of this class. However, while preclinical and clinical studies evaluating combinatorial strategies to maintain the inactivation of KRASG12C have proven that adaptive feedback can be overcome through combinations, the acquired resistance mechanisms remain unclear. In this study, we examine the adaptive and acquired response to KRASG12C inhibition using PDX-CRC models. Methods: We treated three KRASG12C PDX-CRC cell lines (B8182, C1047, and F3008) with sotorasib, panitumumab, and the combo of the two drugs for 6h and 24h. We compare their response to untreated samples to understand the adaptive response over time. Adaptive response to treatment was assessed by measuring the pERK and pEGFR response via western blots. We also treated two KRASG12C PDX-CRC mouse models, B8026 and C1177, with sotorasib, panitumumab, trametinib, as well as doublet and triplet combos with sotorasib. We then assessed treatment response by measuring tumor volume. To develop PDX-CRC models that acquire resistance to sotorasib, we treated the mice continuously with sotorasib over time until we observed noticeable tumor growth. Results: B8182, C1047, and F3008 all show adaptive response to sotorasib. However, while the source of adaptive response is not clear, our data suggests that EGFR may not be the driver in all three cell lines. In our PDX-CRC mouse models, both B8026 and C1177 are responsive to sotorasib and panitumumab. However, C1177 was not responsive to trametinib. Both models however are responsive to doublet combos of sotorasib with either agent, with triplet combo providing the greatest effectiveness in reducing tumor volume. Additionally, B8026 and C1177 PDX-CRC models developed acquired resistance to sotorasib. Conclusion: KRASG12C inhibitors are only modestly active in CRC. Treatment of sotorasib in KRASG12C PDX-CRC cell lines showed that EGFR may not be the primary mediator of adaptive resistance in all models. However, inactivation of KRASG12C can be maintained through combinations targeting the kinases involved in the feedback mechanisms. Finally, while functional characterization of resistance mechanisms is underway, the mechanisms of resistance to KRASG12C appear to be transcriptomic. Citation Format: Oluwadara Coker, Alexey Sorokin, Kelly Gale, Fengqin Gao, John Paul Shen, Lawrence Kwong, Ji Wu, Hey Min Lee, Melanie Woods, Oscar Villareal, Scott Kopetz. Oncogenic KRASG12C dependency in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB264.