Turning Point Therapeutics’ Lead Drug Candidate Repotrectinib Increases Effectiveness of KRAS-G12C and MEK Inhibitors in Preclincal KRAS Cancer Models
The studies were included as part of three poster presentations at today’s virtual annual meeting of the
“Feedback reactivation and bypass signaling may limit the efficacy of KRAS-G12C and MEK inhibitors against KRAS-driven tumors, and our encouraging preclinical data shows how repotrectinib has the potential to increase the anti-tumor effects by inhibiting SRC, FAK and JAK2 signaling,” said
“In addition, we are excited to share for the first time preclinical data for our fourth drug candidate, TPX-0131, a next generation ALK inhibitor in IND enabling studies. We are encouraged by TPX-0131’s preclinical potency against both wildtype ALK and the most common resistant mutations.”
Repotrectinib Combination Studies
The preclinical antitumor activities of repotrectinib in combination with proxy molecules for AMG510, an investigational KRAS-G12C inhibitor, and trametinib, an approved MEK inhibitor were highlighted for the first time in two poster presentations. The studies show repotrectinib’s inhibition of SRC, FAK and JAK2 at therapeutically relevant concentrations, which in combination with AMG510 or trametinib demonstrated a synergistic effect over the single agent by reducing tumor cell growth and enhancing tumor cell death. The repotrectinib-trametinib combination studies were replicated across panels of KRAS mutant non-small cell lung, colorectal and pancreatic cancer cell lines that harbor a spectrum of KRAS mutations.
The frequently mutated Kirsten Rat Sarcoma (KRAS) viral oncogene is associated with a broad range of human cancers, including approximately 25 percent of non-small cell lung, 45 percent of colorectal and 75 percent of pancreatic cancers. Therapeutic targeting of KRAS has proven challenging, in part due to resistance and adaptive upregulation of alternative signaling pathways that promote tumor cell survival, as well as concurrent secretion of various cytokines and growth factors.
In preclinical models, repotrectinib inhibits SRC and FAK signaling, a key pathway for oncogenic resistance, and JAK2, a driver of cytokine secretion pathways.
TPX-0131, a Next-Generation ALK Inhibitor
TPX-0131 has been internally designed with a compact macrocyclic structure to bind completely within the ATP binding site of ALK. In preclinical studies, TPX-0131 potently inhibits wildtype ALK and numerous ALK mutations, in particular the clinically observed G1202R solvent-front mutation and G1202R/L1196M compound mutation.
In cell proliferation assays presented at AACR, TPX-0131 exhibited greater potency against wildtype ALK as compared to proxy molecules for approved front-line ALK inhibitors crizotinib, alectinib, brigatinib and ceritinib, and comparable potency to a proxy molecule for approved ALK inhibitor, lorlatinib. TPX-0131 demonstrated more than 100-fold greater potency against the G1202R solvent-front mutation as compared to proxy molecules for the approved ALK inhibitors. Additionally, TPX-0131 is the most potent inhibitor against a range of EML4-ALK compound mutations while prior generation ALK inhibitors tested have shown moderate to no activity.
Anaplastic lymphoma kinase- (ALK) driven tumors are estimated to represent up to 7 percent of driver oncogenes in non-small cell lung cancer and in one study of patients who develop a resistance mutation, G1202R was reported in approximately 42 percent of patients, and compound mutations have been reported in approximately 35 percent of patients who developed resistance following treatment with lorlatinib.
The three posters presented today are:
Title: Repotrectinib increases effectiveness of KRAS-G12C inhibitors in KRAS-G12C mutant cancer models via simultaneous SRC/FAK/JAK2 inhibition
Abstract Number: 1958
Title: Repotrectinib increases effectiveness of MEK inhibitor trametinib in KRAS mutant cancer models via simultaneous SRC/FAK/JAK2 inhibition
Abstract Number: 1957
Title: TPX-0131: A next generation macrocyclic ALK inhibitor that overcomes ALK resistant mutations refractory to current approved ALK inhibitors
Abstract Number: 5226
Turning Point Therapeutics is a clinical-stage precision oncology company with a pipeline of internally discovered investigational drugs designed to address key limitations of existing cancer therapies. The company’s lead drug candidate, repotrectinib, is a next-generation kinase inhibitor targeting the ROS1 and TRK oncogenic drivers of non-small cell lung cancer and advanced solid tumors. Repotrectinib, which is being studied in a registrational Phase 2 study in adults and a Phase 1/2 study in pediatric patients, has shown antitumor activity and durable responses among kinase inhibitor treatment-naïve and pre-treated patients. The company’s pipeline of drug candidates also includes TPX-0022, targeting MET, CSF1R and SRC, which is being studied in a Phase 1 trial of patients with advanced or metastatic solid tumors harboring genetic alterations in MET; TPX-0046, targeting RET and SRC, which is being studied in a Phase 1/2 trial of patients with advanced or metastatic solid tumors harboring genetic alterations in RET; and TPX-0131, a next-generation ALK inhibitor in IND-enabling studies. Turning Point’s next-generation kinase inhibitors are designed to bind to their targets with greater precision and affinity than existing therapies, with a novel, compact structure that has demonstrated an ability to potentially overcome treatment resistance common with other kinase inhibitors. The company is driven to develop therapies that mark a turning point for patients in their cancer treatment. For more information, visit www.tptherapeutics.com.
Forward Looking Statements
Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements regarding, among other things, the efficacy, safety and therapeutic potential of Turning Point Therapeutics’ drug candidates, repotrectinib and TPX-0131, the results, conduct, progress and timing of Turning Point Therapeutics’ preclinical studies and clinical trials, and plans regarding future development activities. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as “plans”, “will”, “believes,” “anticipates,” “expects,” “intends,” “goal,” “potential” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Turning Point Therapeutics’ current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks and uncertainties associated with Turning Point Therapeutics’ business in general, risks and uncertainties related to the impact of the COVID-19 pandemic to Turning Point’s business and the other risks described in Turning Point Therapeutics’ filings with the
Source: Turning Point Therapeutics, Inc.